Crystal forms and methods of synthesis of (2r, 6r)-hydroxynorketamine and (2s, 6s)-hydroxynorketamine

ABSTRACT

The disclosure provides a method for synthesizing free base forms of (2R,6R)-hydroxynorketamine (HNK) and (2S,6S)-hydroxynorketamine. In an embodiment synthesis of (2R,6R)-hydroxynorketamine (HNK) includes preparation of (R)-norketamine via chiral resolution from racemic norketamine via a chiral resolution with L-pyroglutamic acid. The disclosure also provided crystal forms of the corresponding (2R,6R)-hydroxynorketamine (HNK) and (2S,6S)-hydroxynorketamine hydrochloride salts.

CROSS REFERENCE TO RELATED APPLICATION

This application claims priority from U.S. Provisional Appl. No.62/313,309 filed Mar. 25, 2016, in the United States Patent andTrademark Office, and all the benefits accruing therefrom under 35U.S.C. § 119, the content of which is incorporated herein in itsentirety by reference.

STATEMENT OF GOVERNMENT SUPPORT

This invention was made with government support under Grant NumberNH099345 awarded by the National Institutes of Health. The United Statesgovernment has certain rights in the invention.

BACKGROUND

Ketamine, a drug currently used in human anesthesia and veterinarymedicine, has been shown in clinical studies to be effective in thetreatment of several conditions, including pain, treatment-resistantbipolar depression, major depressive disorder, and other depression andanxiety-related disorders.

However, the routine use of the drug is hindered by unwanted centralnervous system (CNS) effects. Approximately 30% of patients do notrespond to ketamine treatment. Additionally, ketamine treatment isassociated with serious side effects due to the drug's anestheticproperties and abuse potential.

Ketamine analogs have potential advantages over standardantidepressants, as the time to efficacy of ketamine is rapid and takeseffect within hours or minutes, unlike the standard of care selectiveserotonin reuptake inhibitors (SSRIs) which require several weeks tohave an effect. Further, there are patients who respond to theantidepressant effects of ketamine but do not respond to SSRIs.

The compounds (2R,6R)-hydroxynorketamine (HNK) and(2S,6S)-hydroxynorketamine are analogs of ketamine which may be usefulfor treatment of pain, depression, anxiety, and related disorders. Thus,the need for practical and efficient methods of synthesis of thesecompounds, and for stable polymorphs with good pharmaceutical propertiesexists. The present disclosure fulfills this need and providesadditional advantages set forth herein.

FIELD OF THE DISCLOSURE

This disclosure provides free base forms of (2R,6R)-hydroxynorketamine(HNK) and (2S,6S)-hydroxynorketamine, and crystal forms of thecorresponding hydrochloride salts. The disclosure also providespractical and efficient methods for producing (2R,6R)-HNK, (2S,6S)-HNK,(2S,6R)-HNK and (2R,6S)-HNK. The disclosure further provides methods ofproducing 2R,6R-HNK and 2S,6S-HNK crystal forms, crystal forms of thecorresponding hydrochloride salts, and a method of recrystallizing2R,6R-HNK hydrochloride salt.

SUMMARY

The disclosure includes a method for the manufacture of(2R,6R)-hydroxynorketamine or salt thereof and a method for themanufacture of (2S,6S)-hydroxynorketamine, or a salt thereof, the methodcomprising

(i) treating a compound of Formula Ia or Formula Ib with a base, thenwith a trialkylsilylchloride, then with a peroxy compound, and thenoptionally with an acid or a fluoride source, to provide a compound ofFormula IIa if Formula Ia was treated or a compound of Formula IIb ifFormula Ib was treated, wherein the compound of Formula IIa or FormulaIIb contains a carbamate linkage;

and(ii) cleaving the carbamate linkage in the compound of Formula IIa orFormula IIb to provide (2R,6R)-hydroxynorketamine if the carbamatelinkage of the compound of Formula IIa was cleaved, or(2S,6S)-hydroxynorketamine if the carbamate linkage of the compound ofFormula IIb was cleaved

wherein R¹ is C₁-C₆ alkyl, C₁-C₆ haloalkyl, benzyl, 4-methoxybenzyl, or2-trimethylsilylethyl. When R¹ is t-butyl particularly good yields areachieved. The use of chiral starting material provides the advantage ofobtaining an enantiomerically pure product.

The disclosure includes crystalline forms of (2R,6R)-hydroxynorketaminehydrochloride and (2S,6S)-hydroxynorketamine hydrochloride.

The disclosure includes a crystalline form of (2R,6R)-hydroxynorketaminehydrochloride characterized by single crystal parameters approximatelyequal to the following:

cell dimensions comprising a = 7.3549(6) Å alpha = 90° b = 7.4932(5) Åbeta = 96.868(2)° c = 11.3498(8) Å gamma = 90° V = 621.02(8) Å³; andspace group = P 1 21 1, crystal system = monoclinic, molecules per unitcell = 1, density (calculated) = 1.477 Mg/m³.The number in parentheses indicates the uncertainty in the last digitfor the crystal used for this crystal structure determination. However,when multiple crystallizations of 2R,6R-HNK were performed, thevariability in cell dimensions was slightly larger though the 2R,6R-HNKwas still crystallized in the same space group and system. When acrystalline form of 2R,6R-HNK is claimed by unit cell dimensions theclaim encompasses all crystalline forms of 2R,6R-HNK in the same spacegroup and system, having unit cell dimensions a, b, and c as stated+/−0.1 Å and a cell volume as stated +/−2 Å³.

The disclosure also includes a crystalline form of(2S,6S)-hydroxynorketamine hydrochloride characterized by single crystalparameters approximately equal to the following:

cell a = 7.3493(8) Å alpha = 90° dimensions b = 7.4846(8) Å beta =96.866(3)° comprising c = 11.3404(12) Å gamma = 90° V = 619.32(12) Å³;and space group = P 1 21 1, crystal system = monoclinic, molecules perunit cell = 1, density (calculated) = 1.481 Mg/m³.When a crystalline form of 2S,6S-HNK is claimed by unit cell dimensionsthe claim encompasses all crystalline forms of 2S,6S-HNK in the samespace group and system, having unit cell dimensions a, b, and c asstated +/−0.1 Å and a cell volume as stated +/−2 Å³.

The disclosure also includes a crystalline form of(2R,6R)-hydroxynorketamine hydrochloride that contains no detectableamounts of other hydroxynorketamine or hydroxynorketamine saltscrystalline forms as determined by x-ray powder diffraction and acrystalline form of (2S,6S)-hydroxynorketamine hydrochloride thatcontains no detectable amounts of other hydroxynorketamine orhydroxynorketamine salts crystalline forms as determined by x-ray powderdiffraction.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 is a single crystal x-ray structure of (2S,6S)-hydroxynorketaminehydrochloride.

FIG. 2 is a single crystal x-ray structure of (2R,6R)-hydroxynorketaminehydrochloride.

FIG. 3 is an XPRD spectra of ((2R,6R)-hydroxynorketamine hydrochloride.

FIG. 4 is a DSC and TGA of ((2R,6R)-hydroxynorketamine hydrochloride.The DSC profile exhibits an endotherm with an onset at 223.0° C. and amin. The TGA trace exhibits a weight loss of approximately 0.02% from20° C. to 120° C.

DETAILED DESCRIPTION

This disclosure provides the first reported synthetic methods for theproduction of enantiomerically pure 2R,6R-HNK and enantiomerically pure2S,6S-HNK. The (2R,6R)-2-amino-2-(2-chlorophenyl)-6-hydroxycyclohexanone((2R,6R)-hydroxynorketamine (HNK)) ketamine metabolite has the structure

The (2S,6S)-2-amino-2-(2-chlorophenyl)-6-hydroxycyclohexanone((2S,6S)-hydroxynorketamine (HNK)) ketamine metabolite has the structure

This disclosure provides pure crystal forms of(2R,6R)-hydroxynorketamine ((2R,6R)-HNK) and (2S,6S)-hydroxynorketamine((2S,6S)-HNK) hydrochloride salts. The compounds(2R,6R)-hydroxynorketamine and (2S,6S)-hydroxynorketamine can besynthesized using the similar reaction sequences, but starting fromopposite enantiomers of norketamine. Details of the methods forproducing pure HCl crystalline forms and results supporting theseshowings can be found in the Examples section.

Terminology

Compounds disclosed herein are described using standard nomenclature.Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as is commonly understood by one of skill in theart to which this disclosure belongs.

The terms “a” and “an” do not denote a limitation of quantity, butrather denote the presence of at least one of the referenced item. Theterm “or” means “and/or”. The terms “comprising”, “having”, “including”,and “containing” are to be construed as open-ended terms (i.e., meaning“including, but not limited to”). Recitation of ranges of values aremerely intended to serve as a shorthand method of referring individuallyto each separate value falling within the range, unless otherwiseindicated herein, and each separate value is incorporated into thespecification as if it were individually recited herein. The endpointsof all ranges are included within the range and independentlycombinable. All methods described herein can be performed in a suitableorder unless otherwise indicated herein or otherwise clearlycontradicted by context. The use of any and all examples, or exemplarylanguage (e.g., “such as”), is intended merely to better illustrate theinvention and does not pose a limitation on the scope of the inventionunless otherwise claimed. No language in the specification should beconstrued as indicating any non-claimed element as essential to thepractice of the invention as used herein. Unless defined otherwise,technical and scientific terms used herein have the same meaning as iscommonly understood by one of skill in the art to which this inventionbelongs.

The term “alkyl” as used herein refers to a branched or unbranchedsaturated hydrocarbon group typically although not necessarilycontaining 1 to about 24 carbon atoms, such as methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, t-butyl, octyl, decyl, and the like, aswell as cycloalkyl groups such as cyclopentyl, cyclohexyl and the like.Generally, although not necessarily, alkyl groups herein may contain 1to about 18 carbon atoms, and such groups may contain 1 to about 12carbon atoms. The term “lower alkyl” intends an alkyl group of 1 to 6carbon atoms. “Substituted alkyl” refers to alkyl substituted with oneor more substituent groups, and the terms “heteroatom-containing alkyl”and “heteroalkyl” refer to an alkyl substituent in which at least onecarbon atom is replaced with a heteroatom, as described in furtherdetail infra. “haloalkyl” refers to alkyl substituted with one or morehalogens. If not otherwise indicated, the terms “alkyl” and “loweralkyl” include linear, branched, cyclic, unsubstituted, substituted,and/or heteroatom-containing alkyl or lower alkyl, respectively.

“Alkoxy” indicates an alkyl group as defined above with the indicatednumber of carbon atoms attached through an oxygen bridge (—O—). Examplesof alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, and thelike. “Haloalkoxy” refers to alkoxy groups substituted with one or morehalogens.

The term “chiral” refers to molecules, which have the property ofnon-superimposability of the mirror image partner.

The term “carbamate linkage” refers to the linking group “—O—(CO)—NR—”,and “cleaving” the carbamate linkage produces a compound with “RNH—” inplace of the carbamate linkage.

“Stereoisomers” are compounds, which have identical chemicalconstitution, but differ with regard to the arrangement of the atoms orgroups in space.

A “Diastereomer” is a stereoisomer with two or more centers of chiralityand whose molecules are not mirror images of one another. Diastereomershave different physical properties, e.g., melting points, boilingpoints, spectral properties, and reactivities. Mixtures of diastereomersmay separate under high resolution analytical procedures such aselectrophoresis, crystallization in the presence of a resolving agent,or chromatography, using, for example a chiral HPLC column.

“Enantiomers” refer to two stereoisomers of a compound, which arenon-superimposable mirror images of one another. A 50:50 mixture ofenantiomers is referred to as a racemic mixture or a racemate, which mayoccur where there has been no stereoselection or stereospecificity in achemical reaction or process.

The terms “halo” and “halogen” are used in the conventional sense torefer to a chloro, bromo, fluoro or iodo substituent.

Stereochemical definitions and conventions used herein generally followS. P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984)McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S.,Stereochemistry of Organic Compounds (1994) John Wiley & Sons, Inc., NewYork. Many organic compounds exist in optically active forms, i.e., theyhave the ability to rotate the plane of plane-polarized light. Indescribing an optically active compound, the prefixes D and L or R and Sare used to denote the absolute configuration of the molecule about itschiral center(s). The prefixes d and l or (+) and (−) are employed todesignate the sign of rotation of plane-polarized light by the compound,with (−) or l meaning that the compound is levorotatory. A compoundprefixed with (+) or d is dextrorotatory.

A “racemic mixture” or “racemate” is an equimolar (or 50:50) mixture oftwo enantiomeric species, devoid of optical activity. A racemic mixturemay occur where there has been no stereoselection or stereospecificityin a chemical reaction or process.

Where a compound exists in various tautomeric forms, the invention isnot limited to any one of the specific tautomers, but rather includesall tautomeric forms.

The disclosure includes compounds having all possible isotopes of atomsoccurring in the compounds. Isotopes include those atoms having the sameatomic number but different mass numbers. By way of general example, andwithout limitation, isotopes of hydrogen include tritium and deuteriumand isotopes of carbon include ¹¹C, ¹³C, and ¹⁴C.

A “patient” means any human or non-human animal in need of medicaltreatment. Medical treatment can include treatment of an existingcondition, such as a disease or disorder, prophylactic or preventativetreatment in patients known to be at risk for experiencing symptoms ofanxiety or depression, or diagnostic treatment. In some embodiments thepatient is a human patient.

As used herein “halide” is chloride, bromide, or iodide.

HPLC as used herein is high performance liquid chromatography utilizingrefractive index detection with the method described in the ExperimentalSection.

Percent pure (% purity” refers to) the area percentage obtained fromdividing the area of the desired HPLC peak by the sums of areas for thedesired HPLC peak and the HPLC peaks of each reaction impurity andmultiplying this dividend by 100.

“Percent Yield or isolated yield (% yield)’ is the weight of theisolated product(s) divided by the molecular weight of the isolatedproducts divided by the moles of starting material used in the reaction.

“Reaction Impurities” are process related impurities (by products)including all residual starting materials, residual intermediates, andother reaction products other than desired product detected by HPLC. TheFDA uses the term “process related impurities” to describe impuritiesderived from the manufacturing process.

“Stereoselective” is any reaction that results in less than 10% of theundesired epimeric byproduct.

The term “enantioenriched” is used to indicate that, where a compoundmay exist as two or more enantiomers, one of the enantiomers is presentin excess of the other(s). For example, where two enantiomers of acompound are possible, an enantioenriched sample may include greaterthan 50%, greater than 60%, greater than 70%, greater than 75%, greaterthan 80%, greater than 85%, greater than 90%, greater than 95%, orgreater than 99% of one of the enantiomers. A process is“enantioenriching” or “enantioselective” when the process favorsproduction of one enantiomer over production of another enantiomer.Similarly, the term “diastereomerically enriched” is used to indicatethat, where a compound may exist as two or more diastereomers, one ofthe diastereomers is present in excess of the other(s). For example,where two diastereomers of a compound are possible, a diastereomericallyenriched sample may include greater than 50%, greater than 60%, greaterthan 70%, greater than 75%, greater than 80%, greater than 85%, greaterthan 90%, greater than 95%, or greater than 99% of one of thediastereomers. A process is “diastereomerically enriching” or“diastereoselective” when the process favors production of onediastereomer over production of another diaseteomer.

Unless otherwise specified, reference to an atom is meant to includeisotopes of that atom. For example, reference to H is meant to include¹H, ²H (i.e., D) and ³H (i.e., T), and reference to C is meant toinclude ¹²C and all isotopes of carbon (such as ¹³C).

The transitional phrases “comprising,” “consisting essentially of,” and“consisting of,” carry the means accorded these terms by current patentlaw. All embodiments claimed with one of the transitional phases mayalso be claimed using the other transitional phrases. For example, anembodiment claimed with “comprising” as the transitional phrase alsoinclude embodiments that may be claimed with “consisting essentially of” or “consisting of” transitional language and vice versa.

Chemical Description

The structure of (2R,6R)-hydroxynorketamine, IUPAC name(2R,6R)-2-amino-2-(2-chlorophenyl)-6-hydroxycyclohexanone, is:

The structure of (2S,6S)-hydroxynorketamine, IUPAC name(2S,6S)-2-amino-2-(2-chlorophenyl)-6- is hydroxycyclohexanone, is:

The methods herein are stereospecific. This means that if the synthesisstarts with (R)-norketamine, the synthesis will pass through theintermediates Formula Ia and Formula IIa and end with the final product(2R,6R)-hydroxynorketamine ((2R,6R)-HNK). Similarly, if the synthesisstarts with (S)-norketamine, the synthesis will pass through theintermediates Formula Ib and Formula IIb and end with the final product(2S,6S)-hydroxynorketamine ((2S,6S)-HNK). The stereospecific nature ofthe synthetic methods is illustrated below.

The disclosure provides a method for the manufacture of(2R,6R)-hydroxynorketamine or (2S,6S)-hydroxynorketamine, or a saltthereof, the method including generating a compound of Formula Ia orFormula Ib from norketamine

wherein R¹ is C₁-C₆ alkyl, C₁-C₆ haloalkyl, benzyl, 4-methoxybenzyl, ortrimethylsilylethyl. In certain embodiments R¹ is a tert-butyl group.(R)-norketamine can be accessed via chiral resolution from racemicnorketamine via a chiral resolution with L-pyroglutamic acid (or thetartaric acid).

(R)-norketamine can be reacted with a carbamate-forming reagent toproduce the carbamate compound Formula Ia, and (S)-norketamine can bereacted with a carbamate-forming reagent to produce the carbamatecompound Formula Ib. The goal is to produce a carbamate which canprotect the amine during some subsequent steps, and then be deprotectedwhen protection is no longer needed. The carbamate reagent can be adialkyldicarbonate such as di-tert-butyldicarbonate, or analkylhaloformate such as methyl chloroformate, ethyl chloroformate, ortert-butyl chloroformate. The carbamate reagent can be otherchloroformates such as bromoethylchloroformate, benzylchoroformate,4-methoxybenzylchloroformate, or trimethylsilylethylchloroformate. Thisreaction could be performed with a variety of bases, including carbonatebases such as potassium carbonate, lithium carbonate, sodium carbonate,or sodium bicarbonate, hydroxide bases such as lithium hydroxide, sodiumhydroxide, or potassium hydroxide, amine bases such as trimethylamine,trimethylamine, diisopropylethylamine, 1,5-diazabicyclo[4.3.0]non-5-ene(DBN), or 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), or a combination ofthe foregoing, or with no base at all. A wide variety of solvents can beused, including toluene, ethyl acetate, methylene chloride, water, orcombinations of the above.

In an embodiment, generating the compound of Formula Ia or Formula Ibincludes reacting (R)-norketamine with (R¹O₂C)₂O or R¹O₂C—X to generatea compound of Formula Ia, or reacting (S)-norketamine with (R¹O₂C)₂O orR¹ ₂O C—X to generate a compound of Formula Ib; wherein X is a halogen.

In an embodiment, R¹ is tert-butyl, and generating the compound ofFormula Ia includes reacting (R)-norketamine with (tert-butyl-O₂C)₂, andgenerating the compound of Formula Ib includes reacting (S)-norketaminewith (tert-butyl-O₂C)₂O.

The disclosure provides a method for the manufacture of(2R,6R)-hydroxynorketamine or (2S,6S)-hydroxynorketamine, or a saltthereof, the method including treating the compound of Formula Ia orFormula Ib with a strong base, then with a trialkylsilylchloride, thenwith a peroxy compound, and then optionally with an acid or a fluoridesource, to provide a compound of Formula IIa if Formula Ia was treatedor a compound of Formula IIb if Formula Ib was treated

wherein R¹ is C₁-C₆ alkyl, C₁-C₆ haloalkyl, benzyl, 4-methoxybenzyl, ortrimethylsilylethyl.

A compound of Formula IIa or Formula IIb is treated with a base toproduce an intermediate which is believed to be a silyl enol ether, butis used in the next reaction without characterization. While not wantingto be bound by theory, it is believed that the base removes a protonalpha to the carbonyl of the compound of Formula IIa or Formula IIb,generating an enolate, and the enolate then reacts on its oxygen atomwith trialkylsilyl chloride to generate the silyl enol ether.

The disclosure provides methods of producing 2R,6R-HNK and 2S,6S-HNKcrystal forms and crystal forms of the corresponding hydrochloridesalts.

The disclosure also provides a method of obtaining2R,6R-hydroxynorketamine HCl by recrystallization from crude orsemicrude 2R,6R-hydroxynorketamine HCl by means of dissolving the crude2R,6R-hydroxynorketamine HCl in water, then adding acetone at a constantflow rate, which allows for the precipitation of the purified2R,6R-hydroxnorketamine HCl. 2R,6R-hydroxynorketamine has beenpreviously described in the literature and has been noted for itsantidepressant activity. To date, no recrystallization method has beendescribed in the literature for the compound or any of its saltformulations.

The disclosure provides 2R,6R-hydroxynorketamine hydrochloriderecrystallized from crude, semicrude, or purified2R,6R-hydroxynorketamine hydrochloride. Two notable issues may occur inthe late stage formation of 2R,6R-HNK. The first is the presence ofminor byproduct impurities which cannot be removed easily by standardmethods. The second is the “trapping” of organic solvent in the finalsalt formation. These “trapped” solvents cannot be removed by standardmethods (vacuum, heating under vacuum, etc.) which results in a smallpercentage of organic solvent within the final product. Thisrecrystallization method reduces the impurity levels, and criticallyremoves the solvent level within the final 2R,6R-hydroxynorketaminehydrochloride product. Thus the disclosure provides a method ofpurifying 2R,6R-HNK, in which 2R,6R-Hydroxynorketamine hydrochloride isdissolved in an equal mass of water (1 g/1 g). Under magnetic stirring,20 volume equivalents (20 ml per 1 gram) of acetone are added at aconstant flow rate of 0.75 equivalents per minute, while stirring thesolution. The resulting suspension is stirred a further 1.5 hours, thenfiltered, and vacuum dried over 16 hours at room temperature to give thefinal product.

Thus an embodiment of the disclosure includes dissolving solid andpreferably crystalline 2R,6R-HNK hydrochloride in approximately andequal mass of water (1 g compound/1-1.2 grams water), addingapproximately 20 volumes of solvent, or 15 to 25 volumes of solvent,preferably acetone at a constant flow rate, with stirring to form asuspension, followed by filtration to form a filtrate, and vacuumdrying. In certain embodiments the suspension is stirred for 1-4 hours,or 1-2 hours after the addition of solvent is complete. In certainembodiments the filtrate is dried more than 8 hours, more than 12 hours,12-20 hours or about 16 hours.

The disclosure further provides additional synthetic methods that arevariations of the methods described above for producing 2,6-HNK orintermediates useful for producing the various enantiomers of 2,6-HNK.

In one such method, 2-Chlorophenyl cyclopentylketone can be used togenerate (R)- or (S)-norketamine. The disclosure provides a costefficient method for producing 2-chlorophenyl cyclopentylketone startingmaterial by first forming tosyl hydrazide, followed by reaction with2-chlorobenzaldehyde. This reaction is shown in Scheme 1.

This disclosure also provides a method of using diphenyl ether (Scheme2), as opposed to the published route, which uses DowTherm A, to allowthe thermal rearrangement at slightly lower temperatures.

This disclosure provides a modified deprotection of the Rubottomoxidation product that uses formic (Scheme 3). Earlier methods employedtetrabutylammonium fluoride to effect the deprotection.

The disclosure also provides a method of using hydrochloric acid inethyl acetate for the final deprotection (Scheme 4). This directly formsthe desired HCl salt.

The disclosure also provides a synthesis of 2R,6S-hydroxynorketamine and2S,6R-hydroxynorketamine. While the 2R,6S-hydroxynorketamine compound isknown in the literature, the disclosure provides a synthetic route thatis a vast improvement in time, yield, and reproducibility.2R,6S-hydroxynorketamine has been noted to have antidepressant effectsin the forced swim test equal to or greater than that of 2R,6Rhydroxynorketamine, however the stability of 2R,6S-hydroxynorketmine isproblematic. The route (Scheme 5) involves the triflation of enantiopurecompound 8, followed by inversion of the alcohol with the anion ofnitrobenzoic acid. Then cleavage of the nitrobenzoate group and carefuldeprotection of the BOC group yields the desired2R,6S-hydroxynorketamine. This route has also been applied to itsenantiomer.

Thus, the disclosure provides a method of preparing2R,6S-hydroxynorketamine comprising triflation of tert-butyl((1S,3S)-1-(2-chlorophenyl)-3-hydroxy-2-oxocyclohexyl)carbamate (8),followed by inversion of the alcohol with the anion of nitrobenzoicacid, cleavage of the nitrobenzoate group, and removal of the BOCprotecting group to produce 2R,6S-HNK.

The disclosure provides a method of preparing 2R,6S-HNK comprising (i)triflation of entiopure isopropyl((1S,3S)-1-(2-chlorophenyl)-3-hydroxy-2-oxocyclohexyl)carbamate 8 toform(1S,3S)-3-((tert-butoxycarbonypamino)-3-(2-chlorophenyl)-2-oxocyclohexyltrifluoromethanesulfonate. In some embodiments the triflation isconducted in the presence of pyridine in a non-polar solvent such asdichloromethane or other solvent. The reaction may be quenched, forexample by adding sodium bicarbonate. The solvent may be removed byevaporation or other means to form crude triflate 9.

The method of preparing 2R,6S-hydroxynorketamine further comprises (ii)dissolving the crude triflate in DMF or other aprotic solvent such asNMP, followed by addition of 4-nitrobenzoic acid and weak base, such aspotassium carbonate or sodium carbonate. In certain embodiments theproduct is extracted with aqueous solution and the organic phaseevaporated to provide (1S,3R)-3-((tert-butoxycarbonyl)amino)-3-(2-chlorophenyl)-2-oxocyclohexyl 4-nitrobenzoate 10.

This method further comprises (iii) cleavage of the nitrobenzoate groupby dissolving the nitrobenzoate 10 in methanol, or other suitablesolvent such as ethanol, followed by addition of potassium carbonate orother carbonate salt to produce protected 2R,6S-HNK, 11. In someembodiments the protected 2R,6S-HNK is washed with aqueous solution andaqueous saturated salt solution such as saturated sodium chloride.

The method of preparing 2R,6S-HNK further comprises (iv) gentlydeprotecting the protected 2R,6S-HNK, 11, in nonpolar solvent such asDCM and adding acid, such at trifluoroacetic acid. The solvent and acidmay be removed by evaporation, such as rotary evaporation. In someembodiments the product, 2R,6S-HNK, 12, is washed by extraction in ethylacetate and aqueous neutral solution, such as a pH7 potassium phosphatebuffered solution, to the crude material. The purified material may beobtained from the organic phase by evaporation.

Steps (i) to (iv) may also be employed to produce 2S,6R-HNK by startingwith the ((1R,3R)-1-(2-chlorophenyl)-3-hydroxy-2-oxocyclohexyl)carbamate8A enantiomer.

A variety of bases can be used to remove the proton alpha to thecarbonyl in Formula I during the reaction which provides a compound ofFormula II. These bases include strong bases such as lithiumdiisopropylamide, sodium hexamethyldisilazane, potassiumhexamethyldisilazane, or various alkyllithium reagents such assec-butyllithium. Under some conditions weaker bases could be used,including carbonate bases such as potassium carbonate, lithiumcarbonate, sodium carbonate, or sodium bicarbonate, hydroxide bases suchas lithium hydroxide, sodium hydroxide, or potassium hydroxide, aminebases such as trimethylamine, trimethylamine, diisopropylethylamine,1,5-diazabicyclo[4.3.0]non-5-ene (DBN), or1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). When strong bases are used theproton removal should be performed at a temperature below 25° C.,preferably below 0° C., more preferably below −50° C., and can be in arange of −50° C. to −85° C. When weaker bases are used the temperaturecould be in a wide range, from −25° C. to 100° C. The compound ofFormula IIa or Formula IIb should be stirred with the base for a timeperiod sufficient to remove the proton alpha to the carbonyl, and thistime period can be from 5 minutes to 24 hours depending on theconditions and base used. The solvent for this step should be one thatdoes not appreciably react with the base under the conditions used. Whenstrong bases are used, suitable solvents include tetrahydrofuran,diethylether, methyl-tert-butylether, and the like. When weaker basesare used, a wide variety of solvents can be used includingtetrahydrofuran, diethylether, methyl-tert-butylether, methylenechloride, toluene, N,N-dimethylformamide, and the like.

In an embodiment, treating the compound of Formula Ia or Formula Ib witha strong base includes treating the compound of Formula Ia or Formula Ibwith lithium diisopropylamide at a temperature below −50° C.

Following the removal (or possibly during the removal) of the protonalpha to the carbonyl of the compound of Formula Ia or Formula Ib,trialkylsilylchloride is added to react with the intermediate enolateand is believed to form a silyl enol ether. This reaction may beperformed for a period of time from 5 minutes to 24 hours, and at atemperature from −78° C. to 100° C., depending on the conditions. Insome embodiments, the trialkylsilyl chloride is added at the same timeas the base, such that the removal of the proton alpha to the carbonyland the reaction of the resulting enolate with trialkylsilyl chlorideare occurring as a continuous process. The trialkylsilyl chloride can betrimethylsilyl chloride, triethylsilyl chloride, tert-butyldimethylsilylchloride, triisopropylsilyl chloride, and the like.

In an embodiment, the trialkylsilylchloride is trimethylsilyl chloride.

Once the silyl enol ether is formed, it is treated with a peroxycompound and then optionally with an acid or a fluoride source toprovide a compound of Formula IIa or Formula IIb. The peroxy compoundcan be a peroxy acid such as peroxybenzoic acid or peracetic acid, or aperoxide such as dimethyldioxirane, tert-butylhydroperoxide, or hydrogenperoxide. The treatment with the peroxy compound can be performed in avariety of solvents and at a variety of temperatures and reaction times.For example, the treatment with peroxy compound can be performed indichloromethane or chloroform for 5 minutes to 24 hours, and can be at atemperature from −30° C. to 50° C.

In an embodiment, the peroxy compound is meta-chloroperoxybenzoic acid.

In some embodiments following the treatment with peroxy compound, anacid or fluoride source is added to produce a compound of Formula IIa orFormula IIb. While not wanting to be bound by theory, the peroxycompound treatment is believed to generate an alpha-siloxyepoxide, andthe acid or fluoride source cleaves the silicon oxygen bond in the alphasiloxyepoxide to produce an alpha-hydroxyepoxide, which then ring opensto provide alpha-hydroxyketone product Formula IIa or Formula IIb. Thefluoride source can be any fluoride-containing reagent that is capableof breaking the silicon-oxygen bond, and could include sodium fluoride,potassium fluoride, cesium fluoride, tetra-n-butylammonium fluoride,hydrogen fluoride-pyridine, and the like. The addition of a fluoridesource can be performed in a variety of solvents and at a variety oftemperatures and reaction times. For example, the treatment with afluoride source can be performed in tetrahydrofuran, diethylether, ormethyl-tert-butylether, for 5 minutes to 24 hours, and can be at atemperature from −30° C. to 50° C. In some embodiments, thesilicon-oxygen bond can be broken without a fluoride source, such as bytreatment by acid, which could include treatment with hydrochloric,sulfuric, acetic, or trifluoroacetic acids, and the like. In someembodiments, there is no treatment of the alpha siloxyepoxide witheither acid or fluoride source, but the desired product is stillproduced.

In some embodiments, after treatment with peroxy compound the compoundof Formula Ia or Formula Ib is treated with tetra-n-butylammoniumfluoride.

The disclosure provides a method for the manufacture of(2R,6R)-hydroxynorketamine or (2S,6S)-hydroxynorketamine, or a saltthereof, the method including cleaving the carbamate linkage in FormulaIIa or Formula IIb to provide (2R,6R)-hydroxynorketamine if thecarbamate linkage of Formula IIa was cleaved, or(2S,6S)-hydroxynorketamine if the carbamate linkage of Formula IIb wascleaved

wherein R¹ is C₁-C₆ alkyl, C₁-C₆ haloalkyl, benzyl, 4-methoxybenzyl, ortrimethylsilylethyl.

The method of cleaving the carbamate linkage depends on the nature ofR¹. Any carbamate with one of the listed R¹ groups can be cleaved bymild base. If R¹ is tert-butyl, then acid can be used to cleave thetert-butyl carbamate linkage. Acids which can be used for this stepinclude hydrochloric, sulfuric, and acetic acids, such astrifluoroacetic acid. If R¹ is a 2-haloalkyl, such as 2-bromoethyl or2,2,2-trichloroethyl, the carbamate linkage can be cleaved by treatmentwith zinc. If R¹ is benzyl, the carbamate linkage can be cleaved byhydrogenation, if R¹ is 4-methoxybenzyl then the carbamate linkage canbe cleaved by hydrogenation or oxidation, and if R¹ is2-trimethylsilylethyl, then the carbamate linkage can be cleaved bytreatment with fluoride. If any of these treatments produce an acid saltof the product, the resulting salt can then be converted to the freebase using a base, such as potassium carbonate, lithium carbonate,sodium carbonate, or sodium bicarbonate, lithium hydroxide, sodiumhydroxide, potassium hydroxide, trimethylamine, trimethylamine,diisopropylethylamine, 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), or1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). Preferably a carbonate basesuch as sodium bicarbonate is used. The resulting free base can then betreated with hydrochloric acid to produce the (2R,6R)-hydroxynorketaminehydrochloride salt or (2S,6S)-hydroxynorketamine hydrochloride salt .Other acids can be used to make other salts of(2R,6R)-hydroxynorketamine or (2S,6S)-hydroxynorketamine

In an embodiment, R¹ is tert-butyl and cleaving the carbamate linkageincludes treatment with acid.

In an embodiment, R¹ is tert-butyl and cleaving the carbamate linkageincludes treatment with trifluoroacetic acid.

In an embodiment, a hydrochloride salt is manufactured, and the methodadditionally includes treating (2R,6R)-hydroxynorketamine withhydrochloric acid to manufacture (2R,6R)-hydroxynorketaminehydrochloride salt, or treating (2S,6S)-hydroxynorketamine withhydrochloric acid to manufacture (2S,6S)-hydroxynorketaminehydrochloride salt.

In an embodiment, a method for the manufacture of(2R,6R)-hydroxynorketamine, or a salt thereof, includes generating acompound of Formula Ia

treating the compound of Formula Ia with lithium diisopropylamide atbelow −50° C., then with trimethylsilyl chloride, then withmeta-chloroperoxybenzoic acid, and then with tetra-n-utylammoniumbfluoride, to provide a compound of Formula IIa

andcleaving the carbamate linkage in Formula IIa by treatment with acid toprovide (2R,6R)-hydroxynorketamine

wherein R¹ is tert-butyl.

In an embodiment, a hydrochloride salt is manufactured.

In an embodiment, a method for the manufacture of(2S,6S)-hydroxynorketamine, or a salt thereof, includes generating acompound of Formula Ib

treating the compound of Formula Ib with lithium diisopropylamide atbelow −50° C., then with trimethylsilyl chloride, then withmeta-chloroperoxybenzoic acid, and then with tetra-n-butylammoniumfluoride, to provide a compound of Formula IIb

andcleaving the carbamate linkage in Formula IIb, wherein R¹ is tert-butyl,by treatment with acid to provide (2S,6S)-hydroxynorketamine

(2S,6S)-hydroxynorketamine and (2R,6R)-hydroxynorketamine are preparedaccording to the following synthesis in Scheme 6, which shows thesynthesis of (2S,6S)-hydroxynorketamine. The details of (2S,6S)-HNK and(2R,6R)-HNK synthesis are given in Examples 1-8. The compound numbersshown in the (2S,6S)-HNK synthetic route are used in the examples.

Scheme 7 shows the synthetic route for 6,6-dideuteroketaminehydrochloride. The details of the deuteration are provided in Example 9.

In an embodiment, a synthesis shown above in Scheme 7 for(2S,6S)-hydroxynorketamine begins with a chiral resolution of racemicnorketamine 13, which separates racemic norketamine into (S)-norketamine14 and its enantiomer (R)-norketamine. This can be accomplished by useof a chiral resolving agent, such as D-tartaric acid, or by othermethods, which may include chromatography on a chiral medium such as achiral HPLC column. Alternatively, homochiral or enantioenrichednorketamine can be obtained by an enantioselective synthetic method. Thesubsequent steps of Scheme 1 can be applied to (S)-norketamine 13 toeventually produce (2S,6S)-hydroxynorketamine 17, or the steps can beapplied to (R)-norketamine to eventually produce(2R,6R)-hydroxynorketamine

In Scheme 6 (S)-norketamine 14 is reacted with di-tert-butyl-dicarbonatein the presence of potassium carbonate in toluene at 80° C. to producethe Boc-protected compound 15.

Further in Scheme 6, compound 15 in THF at −78° C. is treated withlithium diisopropylamide and trimethylsilyl chloride to produce anintermediate which is believed to be enol ether 16, but is used in thenext reaction without characterization. While not wanting to be bound bytheory, it is believed that the lithium diisopropylamide removes aproton alpha to the carbonyl of compound 15, generating an enolate, andthe enolate then reacts on its oxygen atom with trimethylsilyl chlorideto generate the silyl enol ether 16.

Following the removal of the proton alpha to the carbonyl of 15,trimethylsilylchloride is added to react with the enolate produced from15.

In Scheme 6, once intermediate 16 is formed, it is treated withm-peroxybenzoic acid (mCPBA) and then a fluoride source to providecompound 8, which is Boc-protected (2S,6S)-hydroxynorketamine.

While not wanting to be bound by theory, the mCPBA treatment is believedto generate an alpha-siloxyepoxide, and the fluoride treatment cleavesthe silicon oxygen bond to produce an alpha-hydroxyepoxide, which thenring opens to provide alpha-hydroxyketone 8.

In Scheme 6, compound 8 is treated with trifluoroacetic acid to removethe Boc group and thus deprotect the 2-amino group of(2S,6S)-hydroxynorketamine. The resulting salt is then converted to thefree base using sodium bicarbonate. The resulting free base is thentreated with hydrochloric acid to produce the (2S,6S)-hydroxynorketaminehydrochloride salt 17. Other acids can be used to make other salts of(2S,6S)-hydroxynorketamine.

EXAMPLES General Methods Chemical Methods

All commercially available reagents and solvents were purchased and usedwithout further purification. All microwave reactions were carried outin a sealed microwave vial equipped with a magnetic stir bar and heatedin a Biotage Initiator Microwave Synthesizer. ¹H NMR and ¹³C NMR spectrawere recorded on Varian 400 MHz or Varian 600 MHz spectrometers in CD₃ODor CDCl₃ as indicated. For spectra recorded in CD₃OD, chemical shiftsare reported in ppm with CD₃OD (3.31 MHz) as reference for ¹H NMRspectra and CD₃OD (49.0 MHz) for ¹³C NMR spectra. Alternatively forspectra recorded in CDCl₃, chemical shifts are reported in ppm relativeto deuterochloroform (7.26 ppm for ¹H NMR, 77.23 ppm for ¹³C NMR. Thecoupling constants (J value) are reported as Hertz (Hz). The splittingpatterns of the peaks were described as: singlet (s); doublet (d);triplet (t); quartet (q); multiplet (m) and septet (septet). Sampleswere analyzed for purity on an Agilent 1200 series LC/MS equipped with aLuna C18 (3 mm×75 mm, 3 μm) reversed-phase column with UV detection atλ=220 nm and λ=254 nm. The mobile phase consisted of water containing0.05% trifluoroacetic acid as component A and acetonitrile containing0.025% trifluoroacetic acid as component B. A linear gradient was run asfollows: 0 min 4% B; 7 min 100% B; 8 min 100% B at a flow rate of 0.8mL/min. High resolution mass spectrometry (HRMS) was recorded on Agilent6210 Time-of-Flight (TOF) LC/MS system. Optical rotations were measuredon a PerkinElmer model 341 polarimeter using a 10 cm cell, at 589 nM androom temperature.

Chiral analysis was carried out with an Agilent 1200 series HPLC usingan analytical Chiralpak AD or OJ column (4.6 mm×250 mm; 5 μm). Themobile phase consisted of ethanol containing 0.1% diethylamine ascomponent A and hexanes containing 0.1% diethylamine as component B. Anisocratic gradient was run at 0.4 mL/min with 60% A.

(2R,6R)-hydroxynorketamine hydrochloride and (2S,6S)-hydroxynorketamineare previously described in US 2014/0296241. The synthesis andcrystalline forms disclosed herein have not been previously described.

EXAMPLES Example 1. Chiral Resolution of (S)-(+)-Norketamine (14)

Racemic norketamine (22.7 grams, 101 mmol) (Cayman Chemicals, Ann Arbor,Mich., USA, prepared as described in Hong, S. C. & Davisson, J. N., J.Pharm. Sci. (1982) 71:912-914) was dissolved in 1.1 L ethanol. Then(D)-(R)-(+)-pyroglutamic acid (15.8 g, 0.5 eq., 121 mmol) was added as asolid. The reaction was stirred and heated to reflux for 5 minutes.While heating, a white suspension formed. Once the suspension reachedreflux, it was allowed to cool to room temperature while stirring for 16hours. The reaction was filtered and the white solid was collected. Theresulting white solid was then resuspended in 0.9 L of ethanol and thesuspension was heated to reflux for 5 minutes. The suspension wasallowed to cool to room temperature over 2 hours while stirring. Thesolid was collected by filtration, then suspended a third time inethanol (0.8 L), heated to reflux for 5 minutes, then allowed to cool toroom temperature while stirring. The solid was filtered, collected anddried under vacuum to give (S)-(+)-norketamine D-pyroglutamate. Theenantiomeric excess measured by chiral HPLC to give an enantiomericexcess of 98.3%. The (S)-(+)-norketamine D-pyroglutamate salt wasconverted to the free base by treatment with 1 N aqueous sodiumhydroxide, extraction into ethyl acetate, and removal of the organicsolvent by rotary evaporation to provide (S)-(+)-norketamine as the freebase (from the pyroglutamate salt). (Chiralpak AD column, 60% ethanol inhexanes with 0.01% diethylamine, 1.0 mL, rt: 5.2 min) [α]_(D) ²⁰:(+)-81° (c 1.0, H₂O, D-pyroglutamate salt).

Example 2. Chiral Resolution of (R)-(−)-Norketamine (14A)

(R)-(−)-Norketamine (14A) was produced in an analogous fashion to thatof (S)-(+)-norketamine (2), except that (L)-(S)-(−)-pyroglutamic acidwas used as a chiral resolution agent instead of(D)-(R)-(+)-pyroglutamic acid Chiral HPLC: 98% ee. (Chiralpak AD, 60%ethanol in hexanes, 1 mL/min, rt: 6.8 min.) [α]_(D) ²⁰: (−)-75° (c 1.0,H₂O, L-pyroglutamate salt).

Example 3. Sythesis of (S)-Tert-Butyl(1-(2-Chlorophenyl)-2-Oxocyclohexyl)Carbamate (15)

To a solution of (S)-(+)-norketamine (14) (1.85 g, 8.27 mmol) in toluene(100 mL) was added potassium carbonate (3.43 g, 24.8 mmol) andBOC-anhydride (2.71 g, 12.4 mmol). The reaction was heated to 80° C. andstirred for 16 hours. The reaction was then cooled, extracted with ethylacetate and washed with water. The organic layer was taken and thesolvent removed in vacuo to give the crude product. Purification bysilica gel chromatography (0% to 60% ethyl acetate in hexanes) gave thefinal product (15) as a white solid.

¹H NMR (400 MHz, CDCl₃) δ 7.83 (d, J=8.0 Hz, 1H), 7.42−7.28 (m, 2H),7.28−7.13 (m, 1H), 6.59 (s, 1H), 3.83 (d, J=14.3 Hz, 1H), 2.45−2.36 (m,1H), 2.36−2.25 (m, 1H), 2.04 (ddq, J=11.5, 5.5, 3.0 Hz, 1H), 1.89−1.56(m, 4H), 1.29 (s, 9H).

¹³C NMR (101 MHz, CDCl₃) δ 209.0, 153.4, 135.1, 133.7, 131.5, 130.9,129.2, 126.2, 79.0, 67.1, 39.4, 38.4, 30.8, 28.2, 22.3.

HRMS (ESI+): Expected 346.1186 [M+Na](C₁₇H₂₂ClNO₃Na). Observed 346.1180.[α]_(D) ²⁰: (+)−39.5° (c1.0, CH₂Cl₂).

Example 4. Sythesis of (R)-Tert-Butyl(1-(2-Chlorophenyl)-2-Oxocyclohexyl) Carbamate (15A)

The title compound was prepared in an analogous fashion to(S)-tert-butyl (1-(2-chlorophenyl)-2-oxocyclohexyl)carbamate (15),utilizing (R)-(−)-norketamine (14A) instead of (S)-(+)-norketamine (14).

¹H NMR (400 MHz, CDCl₃) δ 7.85 (d, J=8.0 Hz, 1H), 7.34 (dd, J=8.0, 1.4Hz, 2H), 7.30−7.21 (m, 1H), 6.61 (s, 1H), 3.84 (d, J=14.4 Hz, 1H),2.47−2.37 (m, 1H), 2.38−2.29 (m, 1H), 2.09−2.02 (m, 1H), 1.86−1.62 (m,4H), 1.31 (s, 9H).

¹³C NMR (101 MHz, CDCl₃) δ 209.0, 153.4, 135.0, 133.7, 131.5, 130.8,129.2, 126.2, 79.0, 67.1, 39.4, 38.4, 30.8, 28.2, 22.3.

HRMS (ESI+): Expected 346.1186 [M+Na] (C₁₇H₂₂ClNO₃Na). Observed346.1188. [α]_(D) ²⁰: (−)-60.7° (c 1.0, CH₂Cl₂).

Example 5. Sythesis of Tert-Butyl((1S,3S)-1-(2-Chlorophenyl)-3-Hydroxy-2-Oxocyclohexyl)Carbamate (8)

A solution of (S)-tert-butyl(1-(2-chlorophenyl)-2-oxocyclohexyl)carbamate 15 (6.5 grams) in THF (100mL), was cooled to −78° C. under a nitrogen atmosphere. Lithiumdiisopropylamide (2.0 M in THF/heptane/ethylbenzene, 26 mL, 2.6 eq.) wasadded by syringe. The reaction was stirred 1 hour at −78° C., thenallowed to warm to room temperature for 5 minutes. The reaction wascooled to −78° C., and chlorotrimethylsilane (5.7 grams, 2.6 eq.) wasadded as a neat liquid by syringe. The reaction was stirred for 30minutes at −78° C., and then allowed to warm to room temperature over 30minutes. The reaction was then quenched by being poured into aqueoussaturated ammonium chloride. Ethyl acetate was added to the resultingmixture, the organic phase was separated and the solvent was removed byrotary evaporation to give the crude enol ether 16 as a solid which wasimmediately used without further purification. The enol ether 16 (7.8grams) was dissolved in dichloromethane (100 mL) and cooled to −15° C.(ice-lithium chloride), under a nitrogen atmosphere. 3-Chloroperbenzoicacid (5.0 grams, 1.1 eq.) was then added as a solid. The reaction wasstirred for one hour at −15° C., then the temperature was raised to roomtemperature and an additional 100 mL of dichloromethane was added. Thereaction was stirred a further 0.5 hours. The reaction was then quenchedby being poured into a 50/50 mixture of saturated aqueous sodiumthiosulfate and saturated aqueous sodium bicarbonate. The reaction wasextracted into dichloromethane and the solvent removed by rotaryevaporation. Then tetrahydrofuran (100 mL) was added to the crudematerial. The reaction was cooled to −5° C., and tetra-n-butylbutylammonium fluoride (1.0 M in THF, 25 mL, 1.2 eq. was added). The reactionwas stirred for 2 minutes, before being quenched by addition tosaturated aqueous sodium bicarbonate. Extraction into ethyl acetate,followed by removal of the solvent by rotary evaporation gave the crudefinal product 8. Purification by silica gel chromatography (0% to 70%ethyl acetate in hexanes), gave the purified final product as a solid.

¹H NMR (400 MHz, CDCl₃) δ 7.80 (d, J=7.9 Hz, 1H), 7.34 (ddd, J=8.8, 7.1,1.4 Hz, 2H), 7.29−7.18 (m, 1H), 6.60 (s, 1H), 4.12 (dd, J=11.8, 6.7 Hz,1H), 3.87 (d, J=14.3 Hz, 1H), 3.38 (s, 1H), 2.36 (ddq, J=13.1, 6.5, 3.2Hz, 1H), 1.74 (ddt, J=7.8, 5.7, 2.8 Hz, 2H), 1.69−1.59 (m, 1H),1.59−1.40 (m, 1H), 1.30 (s, 9H).

¹³C NMR (101 MHz, CDCl₃) δ 209.9, 153.3, 134.1, 133.8, 131.4, 131.0,129.7, 126.3, 79.4, 72.4, 66.7, 40.4, 38.8, 28.2, 19.6.

HRMS (ESI+): Expected 362.1135 [M+Na] (C₁₇H₂₂ClNO₄Na). Observed362.1134. [α]_(D) ²⁰: (+)-60.7° (c1.0, CHCl₃).

Example 6. Synthesis of Tert-Butyl((1R,3R)-1-(2-Chlorophenyl)-3-Hydroxy-2-Oxocyclohexyl)Carbamate (8A)

The title compound was prepared in an analogous fashion to (tert-butyl((1S,3S)-1-(2-chlorophenyl)-3-hydroxy-2-oxocyclohexyl)carbamate 5 byutilizing (R)-tert-butyl (1-(2-chlorophenyl)-2-oxocyclohexyl)carbamateinstead of the S-enantiomer.

¹H NMR (400 MHz, CDCl₃) δ 7.80 (d, J=7.9 Hz, 1H), 7.34 (dd, J=8.5, 6.9Hz, 2H), 7.32−7.21 (m, 1H), 6.60 (s, 1H), 4.12 (ddd, J=11.5, 8.9, 6.3Hz, 1H), 3.92−3.83 (m, 1H), 3.37 (d, J=6.5 Hz, 1H), 2.36 (ddq, J=13.0,6.5, 3.2 Hz, 1H), 1.74 (dq, J=6.4, 3.2, 2.5 Hz, 2H), 1.63 (dq, J=16.8,9.2, 8.2 Hz, 1H), 1.59−1.40 (m, 1H), 1.30 (s, 9H).

¹³C NMR (101 MHz, CDCl₃) δ 209.9, 153.3, 134.1, 133.8, 131.4, 131.0,129.7, 126.3, 79.4, 72.4, 66.7, 40.4, 38.8, 28.2, 19.5.

HRMS (ESI+): Expected 362.1135 [M+Na] (C₁₇H₂₂ClNO₄Na). Observed362.1134. [α]_(D) ²⁰: (−)-63.7° (c 1.0, CHCl₃).

Example 7. Sythesis of(2S,6S)-(+)-2-Amino-2-(2-Chlorophenyl)-6-HydroxycyclohexanoneHydrochloride ((2S,6S)-(+)-Hydroxynorketamine Hydrochloride) (17)

To a solution of tert-butyl((1S,3S)-1-(2-chlorophenyl)-3-hydroxy-2-oxocyclohexyl)carbamate 8 (4.85grams) in dichloromethane (10 mL) was added trifluoroacetic acid (11.0mL, 10 eq.). The reaction was stirred at room temperature for 1 hour.The solvent and trifluoroacetic acid (TFA) were then removed by rotaryevaporation. The resulting TFA salt was dissolved in water, washed witha 50/50 mixture of saturated aqueous sodium bicarbonate and saturatedaqueous potassium carbonate solution, and extracted with ethyl acetate(2×) to give the free base. The ethyl acetate was removed by rotaryevaporation. Ethyl acetate (4 mL) was added and HCl in dioxane (4.0 M,6.0 mL) was added. A white solid crashed out. The suspension wasagitated for 30 seconds and then the solid was filtered off and driedunder vacuum to give the desired final product (17).

¹H NMR (400 MHz, MeOD) δ 7.92−7.81 (m, 1H), 7.66−7.50 (m, 3H), 4.28 (dd,J=11.7, 6.6 Hz, 1H), 3.19 (dd, J=14.0, 3.0 Hz, 1H), 2.30 (dddd, J=12.2,6.6, 4.1, 2.3 Hz, 1H), 1.80−1.70 (m, 2H), 1.68−1.52 (m, 2H).

¹³C NMR (100 MHz, MeOD): δ 206.8, 134.0, 132.1, 131.6, 130.5, 130.0,128.3, 73.0, 67.0, 38.4, 37.1, 18.7.

Chiral HPLC: 98.3% ee (Chiralpak AD column, 60% ethanol in hexanes, 1.0mL/min, rt=6.0 min.)

HRMS (ESI+): Expected 240.0786 [M+H] (C₁₂H₁₅ClNO₂). Observed 240.0782.[α]_(D) ²⁰: (+)-95° (c 1.0, H₂O).

Example 8. Sythesis of(2R,6R)-(−)-2-Amino-2-(2-Chlorophenyl)-6-HydroxycyclohexanoneHydrochloride (17A)

((2R,6R)-(−)-hydroxynorketamine hydrochloride)

The title compound was prepared in an analogous fashion to that of(2S,6S)-(+)-hydroxynorketamine hydrochloride by utilizing tert-butyl((1R,3R)-1-(2-chlorophenyl)-3-hydroxy-2-oxocyclohexyl)carbamate (17A)instead of the S,S-enantiomer.

¹H NMR (400 MHz, MeOD): δ 7.94−7.83 (m, 1H), 7.62−7.53 (m, 3H), 4.29(dd, J=11.6, 6.7 Hz, 1H), 3.19 (dd, J=14.0, 3.0 Hz, 1H), 2.30 (dddd,J=12.2, 6.6, 4.1, 2.3 Hz, 1H), 1.99−1.82 (m, 2H), 1.82−1.56 (m, 2H)

¹³C NMR (100 MHz, MeOD): δ 206.8, 134.0, 132.1, 131.6, 130.5, 130.1,128.3, 73.3, 67.0, 38.4, 37.2, 18.7

Chiral HPLC: 98.3% ee (Chiralpak AD column, 60% ethanol in hexanes, 1.0mL/min, rt=7.9 min)

HRMS (ESI+): Expected 262.0605 [M+Na] (C₁₂H₁₄ClNO₂Na). Observed 262.0605[α]D²⁰: (−)-92° (c 1.0, H₂O).

Example 9. Synthesis of 6,6-Dideuterkoketamine Hydrochloride (19)

Sodium deuteroxide (30% in deuterium oxide, 3.0 mL) was added to asolution of racemic ketamine hydrochloride (0.80 grams, 2.9 mmol) in amixture of tetrahydrofuran (8.0 mL) and deuterium oxide (3.0 mL). Thereaction was heated by microwave irradiation in a sealed vial to 120° C.for 2 hours. The reaction was cooled, extracted with ethyl acetate andwashed with saturated aqueous sodium bicarbonate. The organic phase wastaken and the solvent removed by rotary evaporation to give the crudeproduct. Purification by reverse phase liquid chromatography (5% to 95%acetontrile in water with 0.1% trifluoroacetic acid) gave the purifiedTFA salt. The free base was formed and isolated by washing the TFA saltwith saturated aqueous sodium bicarbonate and extraction with ethylacetate. The HCl salt was formed by the addition of HCl (4.0 M indioxane), and filtration of the resulting white solid, to provide thetitle compound as a white solid.

¹H NMR (400 MHz, MeOD): δ 7.94−7.88 (m, 1H), 7.66−7.57 (m, 3H),3.41−3.34 (m, 1H), 2.38 (s, 3H), 2.27−2.20 (m, 1H), 1.93−1.83 (m, 2H),1.83−1.69 (m, 2H).

¹³C NMR (600 MHz, MeOD): δ 208.6, 136.1, 134.1, 133.6, 133.5, 129.9,129.4, 73.8, 40.3 (septet, J_(C-D)=21 Hz, 1C), 37.6, 31.2, 28.1, 23.0.

HRMS (ESI+): Expected 240.1119 [M+H], (C₁₃H₁₅D₂ClNO). Observed 240.1120.

Example 10. X-ray Crystallography of (2S,6S) -(+)-HydroxynorketamineHydrochloride

The single crystal X-ray diffraction studies were carried out on aBruker Kappa APEX-II CCD diffractometer equipped with Mo K_(α) radiation(λ=0.71073 Å). Crystals of the subject compound were grown by slowevaporation of a 50/50 Dichloroethane/Methanol solution. A0.227×0.215×0.106 mm piece of a colorless block was mounted on aCryoloop with Paratone oil. Data were collected in a nitrogen gas streamat 100(2) K using ϕ and

scans. Crystal-to-detector distance was 40 mm and exposure time was 5seconds per frame using a scan width of 2.0°. Data collection was 100%complete to 25.00° in θ. A total of 9466 reflections were collectedcovering the indices, −9<=h<=9, −9<=k<=9, −14<=l<=14. 2949 reflectionswere found to be symmetry independent, with a R_(int) of 0.0376.Indexing and unit cell refinement indicated a primitive, monocliniclattice. The space group was found to be P2₁. The data were integratedusing the Bruker SAINT software program and scaled using the SADABSsoftware program. Solution by direct methods (SHELXT) produced acomplete phasing model consistent with the proposed structure.

All nonhydrogen atoms were refined anisotropically by full-matrixleast-squares (SHELXL-2014). All carbon bonded hydrogen atoms wereplaced using a riding model. Their positions were constrained relativeto their parent atom using the appropriate HFIX command in SHELXL-2014.All other hydrogen atoms (H-bonding) were located in the difference map.Their relative positions were restrained using DFIX commands and theirthermals freely refined. The absolute stereochemistry of the moleculewas established by anomalous dispersion using the Parson's method with aFlack parameter of −0.001. A depiction of the crystal structure is shownin FIG. 1. Crystallographic data are summarized in Tables 1-6.

TABLE 1 Crystal data and structure refinement for(2S,6S)-hydroxynorketamine hydrochloride Property Result Temperature100.0 K Wavelength 0.71073 Å Crystal system Monoclinic Space group P 121 1 Unit cell dimensions a = 7.3493(8) Å α = 90°. b = 7.4846(8) Å β =96.866(3)°. c = 11.3404(12) Å γ = 90°. Volume 619.32(12) Å³ Z   2Density (calculated) 1.481 Mg/m³ Absorption coefficient 0.513 mm⁻¹F(000)  288 Crystal size 0.227 × 0.215 × 0.106 mm³ Crystal color, habitColorless Block Theta range for data collection 1.809 to 28.411° Indexranges −9 <= h <= 9, −9 <= k <= 9, −14 <= 1 <= 14 Reflections collected9466 Independent reflections 2949 [R(int) = 0.0376] Completeness totheta = 25.000° 100.0% Absorption correction Semi-empirical fromequivalents Max. and min. transmission 0.0962 and 0.0677 Refinementmethod Full-matrix least-squares on F² Data/restraints/parameters2949/5/170 Goodness-of-fit on F²   1.075 Final R indices [I > 2sigma(I)]R1 = 0.0239, wR2 = 0.0624 R indices (all data) R1 = 0.0245, wR2 = 0.0629Absolute structure parameter 0.00(2) Extinction coefficient n/a Largestdiff. peak and hole 0.287 and −0.204 e · Å⁻³

TABLE 2 Atomic coordinates (×10⁴) and equivalent isotropic displacementparameters (Å² × 10³) for (2S,6S)-hydroxynorketamine hydrochloride.U(eq) is defined as one third of the trace of the orthogonalized U^(ij)tensor. x y Z U(eq) Cl(1) 6563(1) 1930(1) 1363(1) 22(1) O(1) 5226(2)2952(2) 3850(1) 19(1) O(2) 1922(2) 4022(2) 2743(1) 19(1) N(1) 8564(2)4290(2) 3690(2) 16(1) C(1) 5225(2) 4235(3) 3197(2) 15(1) C(2) 3480(2)5092(2) 2626(2) 16(1) C(3) 3299(3) 6901(3) 3233(2) 18(1) C(4) 4997(3)8055(3) 3174(2) 19(1) C(5) 6740(2) 7066(3) 3678(2) 17(1) C(6) 6981(2)5272(3) 3034(2) 14(1) C(7) 7326(2) 5480(3) 1734(2) 15(1) C(8) 7195(3)4052(3) 939(2) 17(1) C(9) 7583(3) 4231(3) −224(2) 21(1) C(10) 8130(3)5875(3) −621(2) 24(1) C(11) 8284(3) 7311(3) 146(2) 23(1) C(12) 7907(3)7117(3) 1311(2) 19(1) Cl(2) 376(1) 481(1) 3708(1) 18(1)

TABLE 3 Bond lengths [Å] and angles [°] for (2S,6S)-hydroxynorketaminehydrochloride Bond Bond Length (Å) Bonds in Angle Bond Angle (°)Cl(1)-C(8) 1.739(2) C(2)-O(2)-H(2) 113(2) O(1)-C(1) 1.213(3)H(1A)-N(1)-H(1B) 105(2) O(2)-H(2) 0.90(2) H(1A)-N(1)-H(1C) 109(2)O(2)-C(2) 1.417(2) H(1B)-N(1)-H(1C) 103(2) N(1)-H(1A) 0.937(19)C(6)-N(1)-H(1A) 110.7(17) N(1)-H(1B) 0.93(2) C(6)-N(1)-H(1B) 115.3(16)N(1)-H(1C) 0.94(2) C(6)-N(1)-H(1C) 112.4(16) N(1)-C(6) 1.496(2)O(1)-C(1)-C(2) 122.48(16) C(1)-C(2) 1.509(3) O(1)-C(1)-C(6) 122.31(18)C(1)-C(6) 1.536(2) C(2)-C(1)-C(6) 114.63(16) C(2)-H(2A) 1.0000O(2)-C(2)-C(1) 112.02(15) C(2)-C(3) 1.532(3) O(2)-C(2)-H(2A) 109.1C(3)-H(3A) 0.9900 O(2)-C(2)-C(3) 110.04(15) C(3)-H(3B) 0.9900C(1)-C(2)-H(2A) 109.1 C(3)-C(4) 1.526(3) C(1)-C(2)-C(3) 107.38(16)C(4)-H(4A) 0.9900 C(3)-C(2)-H(2A) 109.1 C(4)-H(4B) 0.9900C(2)-C(3)-H(3A) 109.3 C(4)-C(5) 1.529(3) C(2)-C(3)-H(3B) 109.3C(5)-H(5A) 0.9900 H(3A)-C(3)-H(3B) 108.0 C(5)-H(5B) 0.9900C(4)-C(3)-C(2) 111.40(15) C(5)-C(6) 1.548(3) C(4)-C(3)-H(3A) 109.3C(6)-C(7) 1.534(3) C(4)-C(3)-H(3B) 109.3 C(7)-C(8) 1.394(3)C(3)-C(4)-H(4B) 109.4 C(7)-C(12) 1.401(3) C(3)-C(4)-C(5) 111.26(16)C(8)-C(9) 1.389(3) H(4A)-C(4)-H(4B) 108.0 C(9)-H(9) 0.9500C(5)-C(4)-H(4A) 109.4 C(9)-C(10) 1.386(3) C(5)-C(4)-H(4B) 109.4C(10)-H(10) 0.9500 C(4)-C(5)-H(5A) 109.1 C(10)-C(11) 1.379(3)C(4)-C(5)-H(5B) 109.1 C(11)-H(11) 0.9500 C(4)-C(5)-C(6) 112.43(16)C(11)-C(12) 1.389(3) H(5A)-C(5)-H(5B) 107.8 C(12)-H(12) 0.9500C(6)-C(5)-H(5A) 109.1 C(6)-C(5)-H(5B) 109.1 N(1)-C(6)-C(1) 107.84(15)N(1)-C(6)-C(5) 108.54(15) N(1)-C(6)-C(7) 108.62(14) C(1)-C(6)-C(5)103.68(14) C(7)-C(6)-C(1) 113.84(15) C(7)-C(6)-C(5) 114.01(16)C(8)-C(7)-C(6) 122.52(18) C(8)-C(7)-C(12) 116.72(18) C(12)-C(7)-C(6)120.65(18) C(7)-C(8)-Cl(1) 121.42(15) C(9)-C(8)-Cl(1) 116.29(17)C(9)-C(8)-C(7) 122.29(19) C(8)-C(9)-H(9) 120.2 C(10)-C(9)-C(8) 119.6(2)C(10)-C(9)-H(9) 120.2 C(9)-C(10)-H(10) 120.3 C(11)-C(10)-C(9) 119.47(19)C(11)-C(10)-H(10) 120.3 C(10)-C(11)-H(11) 119.7 C(10)-C(11)-C(12)120.5(2) C(12)-C(11)-H(11) 119.7 C(7)-C(12)-H(12) 119.3 C(11)-C(12)-C(7)121.4(2) C(11)-C(12)-H(12) 119.3

TABLE 4 Anisotropic displacement parameters (Å² × 10³)for(2S,6S)-hydroxynorketamine hydrochloride. The anisotropicdisplacement factor exponent takes the form: −2π²[h² a*²U¹¹ + . . . + 2h k a* b* U¹²] U¹¹ U²² U³³ U²³ U¹³ U¹² Cl(1) 27(1) 16(1) 22(1) −3(1) 3(1) −2(1)  O(1) 19(1) 18(1) 21(1) 3(1) 5(1) 0(1) O(2) 13(1) 20(1) 23(1)2(1) 3(1) −1(1)  N(1) 14(1) 18(1) 15(1) 0(1) 2(1) 1(1) C(1) 16(1) 15(1)14(1) −4(1)  4(1) 1(1) C(2) 14(1) 16(1) 18(1) 1(1) 3(1) −1(1)  C(3)17(1) 17(1) 21(1) −2(1)  3(1) 4(1) C(4) 20(1) 15(1) 22(1) −1(1)  2(1)1(1) C(5) 18(1) 15(1) 18(1) −2(1)  1(1) 1(1) C(6) 13(1) 14(1) 15(1)−1(1)  2(1) 1(1) C(7) 12(1) 18(1) 16(1) 2(1) 1(1) 2(1) C(8) 15(1) 18(1)18(1) 1(1) 1(1) 1(1) C(9) 19(1) 28(1) 16(1) −2(1)  1(1) 4(1) C(10) 21(1)35(1) 17(1) 7(1) 3(1) 5(1) C(11) 18(1) 27(1) 24(1) 8(1) 4(1) 1(1) C(12)16(1) 20(1) 21(1) 2(1) 2(1) −2(1)  Cl(2) 20(1) 16(1) 18(1) 0(1) 1(1)1(1)

TABLE 5 Hydrogen coordinates (×10⁴) and isotropic displacementparameters (Å² × 10³) for (2S,6S)-hydroxynorketamine hydrochloride. x yz U(eq) H(2) 2200(40) 3010(30) 3160(30) 40(9) H(1A) 9650(30) 4530(40)3360(20) 23(6) H(1B) 8460(30) 3060(30) 3690(20) 19(6) H(1C) 8730(40)4570(40) 4506(19) 23(6) H(2A) 3575 5291 1764 19 H(3A) 2209 7535 2840 22H(3B) 3116 6706 4074 22 H(4A) 4882 9168 3631 23 H(4B) 5086 8387 2338 23H(5A) 6695 6831 4533 20 H(5B) 7815 7836 3604 20 H(9) 7474 3232 −745 25H(10) 8397 6012 −1416 29 H(11) 8650 8442 −124 27 H(12) 8047 8115 1832 23

TABLE 6 Hydrogen bonds for (2S,6S)-hydroxynorketamine hydrochloride [Åand °]. D-H . . . A d(D-H) d(H . . . A) d(D . . . A) <(DHA) O(2)-H(2) .. . Cl(2) 0.90(2) 2.44(3) 3.1317(16) 133(3) N(1)-H(1A) . . .O(2)#10.937(19) 1.92(2) 2.814(2) 158(2) N(1)-H(1B) . . . 0.93(2) 2.39(2)3.1460(19) 139(2) Cl(2)#1 N(1)-H(1C) . . . 0.94(2) 2.16(2) 3.0925(18)168(2) Cl(2)#2 Symmetry transformations used to generate equivalentatoms: #1x + 1, y, z #2−x + 1, y + ½, −z + 1

Example 11. X-Ray Crystallography of (2R,6R)-HydroxynorketamineHydrochloride

The single crystal X-ray diffraction studies were carried out on aBruker Kappa APEX-II CCD diffractometer equipped with Mo K_(α) radiation(λ=0.71073 Å). Crystals of the subject compound were grown by slowevaporation of an isopropanol solution. A 0.157×0.131×0.098 mm piece ofa colorless block was mounted on a Cryoloop with Paratone oil. Data werecollected in a nitrogen gas stream at 100(2) K using A 0.157×0.131×0.098mm piece of a colorless block was mounted on a Cryoloop with Paratoneoil. Data were collected in a nitrogen gas stream at 100(2) K using ϕand

scans. Crystal-to-detector distance was 40 mm and exposure time was 3seconds per frame using a scan width of 2.0°. Data collection was 100%complete to 25.00° in θ. A total of 7618 reflections were collectedcovering the indices, −9<=h<=9, −9<=k<=9, −14<=l<=14. 2927 reflectionswere found to be symmetry independent, with a R_(int) of 0.0350.Indexing and unit cell refinement indicated a primitive, monocliniclattice. The space group was found to be P2₁. The data were integratedusing the Bruker SAINT software program and scaled using the SADABSsoftware program. Solution by direct methods (SHELXT) produced acomplete phasing model consistent with the proposed structure.

All nonhydrogen atoms were refined anisotropically by full-matrixleast-squares (SHELXL-2014). All carbon bonded hydrogen atoms wereplaced using a riding model. Their positions were constrained relativeto their parent atom using the appropriate HFIX command in SHELXL-2014.

All other hydrogen atoms (H-bonding) were located in the difference map.Their relative positions were restrained using DFIX commands and theirthermals freely refined. The absolute stereochemistry of the moleculewas established by anomalous dispersion using the Parson's method with aFlack parameter of 0.023(32). A depiction of the crystal structure isshown in FIG. 2. Crystallographic data are summarized in Tables 7-12.

TABLE 7 Crystal data and structure refinement for(2R,6R)-hydroxynorketamine hydrochloride Property Result Temperature100.0 K Wavelength 0.71073 Å Crystal system Monoclinic Space group P 121 1 Unit cell dimensions a = 7.3549(6) Å α = 90°. b = 7.4932(5) Å β =96.868(2)°. c = 11.3404(12) Å γ = 90°. Volume 621.02(8) Å³ Z   2 Density(calculated) 1.477 Mg/m³ Absorption coefficient 0.511 mm⁻¹ F(000)  288Crystal size 0.157 × 0.131 × 0.098 mm³ Crystal color, habit ColorlessBlock Theta range for data collection 1.807 to 28.290° Index ranges −9<= h <= 9, −9 <= k <= 9, −14 <= 1 <= 14 Reflections collected 7618Independent reflections 2927 [R(int) = 0.0350] Completeness to theta =25.000° 100.0% Absorption correction Semi-empirical from equivalentsMax. and min. transmission 0.0962 and 0.0687 Refinement methodFull-matrix least-squares on F² Data/restraints/parameters 2927/5/170Goodness-of-fit on F²   1.040 Final R indices [I > 2sigma(I)] R1 =0.0265, wR2 = 0.0659 R indices (all data) R1 = 0.0280, wR2 = 0.0669Absolute structure parameter 0.02(3) Extinction coefficient n/a Largestdiff. peak and hole 0.283 and −0.201 e · Å⁻³

TABLE 8 Atomic coordinates (×10⁴) and equivalent isotropic displacementparameters (Å² × 10³) for (2R,6R)-hydroxynorketamine hydrochloride.U(eq) is defined as one third of the trace of the orthogonalized U^(ij)tensor. x y Z U(eq) Cl(1) 3437(1) 8068(1) 8636(1) 20(1) O(1) 4777(2)7045(2) 6149(1) 18(1) O(2) 8078(2) 5975(2) 7255(2) 18(1) N(1) 1437(2)5707(3) 6311(2) 14(1) C(1) 4777(3) 5763(3) 6802(2) 13(1) C(2) 6518(3)4905(3) 7374(2) 14(1) C(3) 6698(3) 3100(4) 6768(2) 16(1) C(4) 5001(3)1942(3) 6824(2) 17(1) C(5) 3260(3) 2934(3) 6323(2) 16(1) C(6) 3023(3)4721(3) 6968(2) 13(1) C(7) 2670(3) 4523(3) 8268(2) 14(1) C(8) 2804(3)5944(3) 9065(2) 16(1) C(9) 2415(3) 5767(4) 10223(2) 20(1) C(10) 1875(3)4126(4) 10622(2) 23(1) C(11) 1718(3) 2687(3) 9853(2) 21(1) C(12) 2095(3)2883(4) 8689(2) 18(1) Cl(2) 9623(1) 9516(1) 6291(1) 17(1)

TABLE 9 Bond lengths [Å] and angles [°] for (2R,6R)-hydroxynorketaminehydrochloride Bond Bond Length (Å) Bonds in Angle Bond Angle (°)Cl(1)-C(8) 1.743(2) C(2)-O(2)-H(2) 114(2) O(1)-C(1) 1.214(3)H(1A)-N(1)-H(1B) 105(3) O(2)-H(2) 0.90(2) H(1A)-N(1)-H(1C) 105(3)O(2)-C(2) 1.419(3) H(1B)-N(1)-H(1C) 109(3) N(1)-H(1A) 0.92(2)C(6)-N(1)-H(1A) 115.0(18) N(1)-H(1B) 0.94(2) C(6)-N(1)-H(1B) 111.9(18)N(1)-H(1C) 0.95(2) C(6)-N(1)-H(1C) 110.2(17) N(1)-C(6) 1.502(3)O(1)-C(1)-C(2) 122.56(19) C(1)-C(2) 1.508(3) O(1)-C(1)-C(6) 122.52(19)C(1)-C(6) 1.539(3) C(2)-C(1)-C(6) 114.35(19) C(2)-H(2A) 1.0000O(2)-C(2)-C(1) 111.90(18) C(2)-C(3) 1.530(3) O(2)-C(2)-H(2A) 109.2C(3)-H(3A) 0.9900 O(2)-C(2)-C(3) 109.99(17) C(3)-H(3B) 0.9900C(1)-C(2)-H(2A) 109.2 C(3)-C(4) 1.528(3) C(1)-C(2)-C(3) 107.32(18)C(4)-H(4A) 0.9900 C(3)-C(2)-H(2A) 109.2 C(4)-H(4B) 0.9900C(2)-C(3)-H(3A) 109.3 C(4)-C(5) 1.531(3) C(2)-C(3)-H(3B) 109.3C(5)-H(5A) 0.9900 H(3A)-C(3)-H(3B) 108.0 C(5)-H(5B) 0.9900C(4)-C(3)-C(2) 111.61(18) C(5)-C(6) 1.546(3) C(4)-C(3)-H(3A) 109.3C(6)-C(7) 1.535(3) C(4)-C(3)-H(3B) 109.3 C(7)-C(8) 1.393(3)C(3)-C(4)-H(4A) 109.4 C(7)-C(12) 1.401(3) C(3)-C(4)-H(4B) 109.4C(8)-C(9) 1.385(3) C(3)-C(4)-C(5) 111.11(19) C(9)-H(9) 0.9500H(4A)-C(4)-H(4B) 108.0 C(9)-C(10) 1.385(4) C(5)-C(4)-H(4A) 109.4C(10)-H(10) 0.9500 C(5)-C(4)-H(4B) 109.4 C(10)-C(11) 1.383(4)C(4)-C(5)-H(5A) 109.1 C(11)-H(11) 0.9500 C(4)-C(5)-H(5B) 109.1C(11)-C(12) 1.390(3) C(4)-C(5)-C(6) 112.40(18) C(12)-H(12) 0.9500H(5A)-C(5)-H(5B) 107.9 C(6)-C(5)-H(5A) 109.1 C(6)-C(5)-H(5B) 109.1N(1)-C(6)-C(1) 107.57(18) N(1)-C(6)-C(5) 108.39(17) N(1)-C(6)-C(7)108.37(17) C(1)-C(6)-C(5) 103.73(16) C(7)-C(6)-C(1) 114.02(17)C(7)-C(6)-C(5) 114.42(19) C(8)-C(7)-C(6) 122.9(2) C(8)-C(7)-C(12)116.8(2) C(12)-C(7)-C(6) 120.3(2) C(7)-C(8)-Cl(1) 121.18(17)C(9)-C(8)-Cl(1) 116.4(2) C(9)-C(8)-C(7) 122.4(2) C(8)-C(9)-H(9) 120.1C(8)-C(9)-C(10) 119.7(2) C(10)-C(9)-H(9) 120.1 C(9)-C(10)-H(10) 120.3C(11)-C(10)-C(9) 119.4(2) C(11)-C(10)-H(10) 120.3 C(10)-C(11)-H(11)119.8 C(10)-C(11)-C(12) 120.4(2) C(12)-C(11)-H(11) 119.8C(7)-C(12)-H(12) 119.4 C(11)-C(12)-C(7) 121.3(2) C(11)-C(12)-H(12) 119.4

TABLE 10 Anisotropic displacement parameters (Å² × 10³)for(2R,6R)-hydroxynorketamine hydrochloride. The anisotropicdisplacement factor exponent takes the form: −2π²[h² a*²U¹¹ + . . . + 2h k a* b* U¹²] U¹¹ U²² U³³ U²³ U¹³ U¹² Cl(1) 26(1) 15(1) 20(1) −3(1) 3(1) −2(1)  O(1) 18(1) 17(1) 19(1) 4(1) 5(1) 0(1) O(2) 12(1) 19(1) 22(1)3(1) 2(1) −1(1)  N(1) 13(1) 16(1) 14(1) −1(1)  2(1) 1(1) C(1) 13(1)14(1) 13(1) −3(1)  4(1) 0(1) C(2) 13(1) 15(1) 16(1) 1(1) 2(1) −1(1) C(3) 15(1) 15(1) 19(1) −1(1)  2(1) 5(1) C(4) 18(1) 12(1) 21(1) −2(1) 1(1) 1(1) C(5) 16(1) 16(1) 16(1) −3(1)  1(1) 0(1) C(6) 11(1) 14(1) 14(1)0(1) 1(1) 1(1) C(7) 12(1) 18(1) 14(1) 2(1) 1(1) 1(1) C(8) 14(1) 18(1)18(1) 2(1) 1(1) 1(1) C(9) 18(1) 26(1) 16(1) −2(1)  1(1) 4(1) C(10) 18(1)34(2) 16(1) 6(1) 4(1) 3(1) C(11) 17(1) 24(1) 23(1) 8(1) 2(1) 0(1) C(12)15(1) 20(1) 19(1) 1(1) 2(1) −2(1)  Cl(2) 19(1) 15(1) 16(1) 1(1) 1(1)1(1)

TABLE 11 Hydrogen coordinates (×10⁴) and isotropic displacementparameters (Å² × 10³) for (2R,6R)-hydroxynorketamine hydrochloride. x yz U(eq) H(2) 7830(50) 7000(40) 6860(30) 41(10) H(1A) 1540(40) 6930(30)6330(20) 22(8) H(1B) 1270(40) 5410(40) 5500(20) 23(7) H(1C) 340(30)5450(40) 6650(20) 20(7) H(2A) 6423 4708 8236 17 H(3A) 6881 3297 5928 20H(3B) 7788 2467 7160 20 H(4A) 4913 1604 7659 21 H(4B) 5117 834 6364 21H(5A) 2184 2166 6396 19 H(5B) 3304 3172 5468 19 H(9) 2518 6766 10741 24H(10) 1614 3989 11417 27 H(11) 1351 1557 10123 26 H(12) 1960 1887 816821

TABLE 12 Hydrogen bonds for (2R,6R)-hydroxynorketamine hydrochloride [Åand °]. D-H . . . A d(D-H) d(H...A) d(D . . . A) <(DHA) O(2)-H(2) . . .Cl(2) 0.90(2) 2.43(3) 3.1348(18) 135(3) N(1)-H(1A) . . . Cl(2)#1 0.92(2)2.39(3) 3.149(2) 140(2) N(1)-H(1B) . . . Cl(2)#2 0.94(2) 2.16(2)3.095(2) 169(2) N(1)-H(1C) . . . O(2)#1 0.95(2) 1.92(2) 2.816(2) 156(3)Symmetry transformations used to generate equivalent atoms: #1x + 1, y,z #2−x + 1, y + ½, −z + 1

Example 12. PXRD of (2R,6R)-Hydroxynorketamine Hydrochloride

A powder x-ray diffraction spectra of (2R,6R)-hydroxynorketaminehydrochloride is shown in FIG. 3. 5-10 mg of (2R,6R)-hydroxynorketaminehydrochloride was added to a PXRD sample holder.

The Rigaku Smart-Lab X-ray diffraction system was configured forreflection Bragg-Brentano geometry using a line source X-ray beam. Thex-ray source is a Cu Long FineFocus tube that was operated at 40 kV and44 ma. That source provides an incidentbeam profile at the sample thatchanges from a narrow line at high angles to a broad rectangle at lowangles. Beam conditioning slits are used on the line X-ray source toensure that the maximum beam size is less than 10 mm both along the lineand normal to the line. The Bragg-Brentano geometry is a para-focusinggeometry controlled by passive divergence and receiving slits with thesample itself acting as the focusing component for the optics. Theinherent resolution of Bragg-Brentano geometry is governed in part bythe diffractometer radius and the width of the receiving slit used.Typically, the Rigaku Smart-Lab is operated to give peak widths of 0.1°2θ or less. The axial divergence of the X-ray beam is controlled by5.0-degree Soller slits in both the incident and diffracted beam paths.Powder samples were prepared in a low background Si holder using lightmanualpressure to keep the sample surfaces flat and level with thereference surface of the sample holder.

The powder was pressed down gently with the sample flattening tool andthe sample holder was placed in the sample changer. Each sample wasanalyzed from 2 to 40° 2θ using a continuous scan of 6° 2θ per minutewith an effective step size of 0.02° 2θ.

Run Parameters: Soller (inc.) 5.0 deg, IHS 10.0 mm, SS 1.250 deg, DS1.250 deg, Soller (rec) 5.0 deg, RS 0.3 mm, Scan Axis Theta/2-Theta,Mode Continuous, Start (deg) 3.0, Stop (deg) 45.0, Step (deg) 0.020,Speed (deg/min) 2.5, Spin-yes, Voltage (kV) 40, Current (mA) 15. Thespectra demonstrates the following characteristic peaks (2θ).

TABLE 13 No. 2 θ 1 12.1 2 13.6 3 14.1 4 15.1 5 15.6 6 16.9 7 18.0 8 19.29 19.5 10 20.8 11 22.1 12 23.5 13 24.0 14 24.3 15 24.6 16 24.8 17 25.218 26.4 19 27.0 20 27.4 21 27.7 22 28.1 23 28.9 24 29.9 25 30.2 26 31.527 31.9 28 32.4 29 32.7 30 33.5 31 34.1 32 34.7 33 36.5 34 37.1 35 37.736 38.3 37 38.7 38 39.1 39 39.6

Example 13. TGA and DSC of (2R,6R)-Hydroxynorketamine Hydrochloride

Thermogravimetric analysis and differential scanning calorimetry plotsfor (2R,6R)-hydroxynorketamine hydrochloride are shown in FIG. 4. Forthe DSC 1-3 mg of (2R,6R)-HNK was weighed into a TZero pan. A TZero lidwas placed on the pan and gently pressed down. The pan was thentransferred to the DSC for analysis at 10° C./min up to 300° C. A DSCstandard was made by the same procedure but without HNK. For TGAstandard aluminum pan was placed into the platinum TGA pan and the blankwas tared with the instrument. 1-5 mg of (2R,6R)-HNK was added to thestandard aluminum pan and analyzed at 10° C./min up to 300° C. Thesample exhibited a weight loss of 0.02% out to ˜125° C. This weight lossis likely due to residual solvent and suggests the material isanhydrous. An onset of melt was observed at 223.017° C.

Example 14. Synthesis of 2-Chlorophenyl Cyclopentylketone

Compound 1 (4.00 kg, 21.5 mol) is dissolved in MeOH (40.0 L). Compound1-2 (1.90 kg, 22.6 mol, 2.00 L) is then added dropwised in the mixture.After added, the reaction mixture was stirred at 20° C. for 12 h underN₂ atmosphere. TLC (PE:EA=5:1) showed starting material was consumed,and the desired compound was detected. Amounts of precipitate wereformed. The reaction mixture was filtered, and the cake was collected,then dried to give compound 2 (5.00 kg, 19.8 mol, 92.2% yield) as awhite solid.

A solution of compound 1-4 (1.51 kg, 10.8 mol, 1.34 L), compound 2 (3kg, 11.9 mol) and Cs₂CO₃ (5.28 kg, 16.2 mol) in 1,4-dioxane (40.0 L) wasstirred at 100-110° C. for 48 hours. TLC (PE:EA=5:1) showed startingmaterial was consumed, and the desired compound was detected. Thereaction mixture was filtered and concentrated in vacuum to give aresidue. The residue was triturated with PE (20 L) to give compound 3(2.00 kg, crude) as a red oil.

Example 15. Preparation of Norketamine

Compound 4 (300 g, 1.15 mmol, HCl) was dissolved in diphenyl oxide (3.00L), the mixture was stirred at 170-185° C. for 15 min. TLC(PE:EA=1:1,starting material: R_(f)=0.6, product: R_(f)=0.5) showedstarting material was consumed, and one new pot was detected. Thereaction mixture was cooled to 25-30° C., added water (6 L), thenfiltered. The filtrate was extracted with EtOAc (2 L*3). The aqueouslayer was adjusted pH=8-9 with sat Na₂CO₃ solution, then extracted withEtOAc (2 L*2), the combined organic layers were washed with brine (1 L),dried over Na₂SO_(4,) filtered, and the filtrate was concentrated underreduced pressure to give compound 13 (1.10 kg, 61.0% yield) as a yellowsolid.

Example 16. Preparation of Tert-Butyl((1R,3R)-1-(2-Chlorophenyl)-3-Hydroxy-2-Oxocyclohexyl)Carbamate

Compound 6 (200 g, 485 mmol) was dissolved in THF (4.00 L) and H₂O (200mL), and then added to Formic Acid (200 mL, 98% purity), the mixture wasstirred at 15° C. for 1 h. HPLC showed starting material was consumed,and the desired compound was detected. The reaction mixture was quenchedby addition sat.Na₂CO₃(2 L) and sat. NaHCO₃ (2 L), and then extractedwith EtOAc (2 L*3). The combined organic layers were washed with brine(1 L), dried over Na₂SO₄, filtered and concentrated under reducedpressure to give a residue. The residue was purified by columnchromatography (SiO₂, Petroleum ether:Ethyl acetate=20:1 to 8:1) to givea yellow gum. And then the gum was triturated with PE (500 mL) to givecompound 7 (60 g, 169 mmol, 34.8% yield) as a white solid.

Example 17. Deprotection in Ethyl Acetate to Provide2R,6R-Hydroxynorketamine Hydrochloride

Compound 7 (150 g, 441 mmol) was dissolved in EtOAc (2.00 L). HCl/ EtOAc(4 M, 331 mL) was then added to the mixture at 15° C. under N₂. Afteraddition, the reaction mixture was stirred at 15° C. for 12 h. Aprecipitate was formed. TLC (PE:EA=2:1) showed the starting material wasconsumed, and the desired compound was detected. The mixture wasfiltered, washed with EtOAc (1 L), PE (1 L) in return and dried undervacuum to give a white solid. The white solid was combined with otherbatches, then triturated with EtOAc (3.5 L) and MeOH (100 mL) to givecompound 5, 2R,6R-hydroxynorketamine hydrochloride as a white solid.

Example 18. Preparation of(1S,3R)-3-(Tert-Butoxycarbonyl)Amino)-3-(2-Chlorophenyl)-2-Oxocyclohexyl4-Nitrobenzoate (10A)

tert-Butyl((1R,3R)-1-(2-chlorophenyl)-3-hydroxy-2-oxocyclohexyl)carbamate (8A)(2.82 grams, 8.30 mmol) was placed in a round bottom flask with astirbar. Dichloromethane (20 ml) was added, followed by pyridine (1.31grams, 16.6 mmol). The reaction was stirred until all reagentsdissolved, then placed under a nitrogen atmosphere and cooled to 0° C.Then trifluoromethanesulfonic anhydride (1.0 M in dichloromethane, 9.43mL, 9.43 mmol) was added via syringe. The reaction was stirred for 45minutes at 0° C., then quenched by being poured into a solution ofsaturated aqueous sodium bicarbonate. The mixture was extracted withdichloromethane, and the solvent removed by rotary evaporation to givethe crude triflate (9A), which was used without further purification.The triflate was unstable, and required either immediate use or storageat −80° C.

The crude triflate (3.92 grams, 8.3 mmol, based on 100% yield) was thendissolved in dimethylformamide (50 ml). Then 4-nitrobenzoic acid (5.55grams, 33.2 mmol, followed by potassium carbonate (1.15 grams, 8.30mmol) was added. The suspension was stirred vigorously at roomtemperature for 16 hours. The reaction was then poured into a separatoryfunnel containing diethyl ether (200 ml) and water (100 ml). The organicphase was washed twice with water (100 ml) and once with saturatedaqueous sodium chloride (100 ml). The organic phase was taken, and thesolvent removed by rotary evaporation. Purification by silica gelchromatography (0% to 100% ethyl acetate in diethyl ether) provided thetitle compound.

¹H NMR (400 MHz, Chloroform-d) δ 8.23−8.11 (m, 2H), 7.95−7.85 (m, 2H),7.58 (d, J=7.9 Hz, 1H), 7.36−7.27 (m, 1H), 7.27−7.20 (m, 1H), 7.20−7.14(m, 1H), 5.99 (s, 1H), 5.93 (dd, J=8.7, 4.9 Hz, 1H), 3.19−3.09 (m, 1H),2.43−2.31 (m, 2H), 2.27−2.00 (m, 3H), 1.32 (s, 9H).

¹³C NMR (101 MHz, CDCl₃) δ 199.5, 163.3, 153.9, 150.5, 136.2, 134.8,133.6, 131.3, 130.9, 129.7, 128.6, 126.4, 123.3, 80.5, 76.2, 68.5, 37.9,33.8, 28.0, 18.9. HRMS (ESI+): Expected 511.1242 [M+Na⁺] (C₂₄H₂₅ClN₂NaO₇⁺). Observed 511.1248. [α]_(D) ²⁰: +9.5° (c 1.0, chloroform).

Example 19. Preparation of Tert-Butyl((1R,3S)-1-(2-Chlorophenyl)-3-Hydroxy-2-Oxocyclohexyl)Carbamate (11A)

(1S,3R)-3-((tert-butoxycarbonyl)amino)-3-(2-chlorophenyl)-2-oxocyclohexyl4-nitrobenzoate (10A) (2.00 grams, 4.09 mmol) was dissolved in methanol(50 ml). The reaction was cooled to 0° C., and potassium carbonate(0.565 mg, 4.09 mmol) was added. The reaction was stirred for 30 minutesat 0° C. The reaction was then quenched by being poured into an aqueoussolution of saturated sodium bicarbonate. The mixture was extracted withethyl acetate, the organic layer was taken, and the solvent removed byrotary evaporation. Purification by silica gel chromatography (0% to100% ethyl acetate in hexanes) gave the desired product (11A) in 65%yield.

¹H NMR (400 MHz, Chloroform-d) δ 7.45−7.40 (m, 1H), 7.40−7.33 (m, 1H),7.33−7.23 (m, 2H), 5.28 (s, 1H), 4.65 (dd, J=12.1, 6.5 Hz, 1H),3.02−2.88 (m, 1H), 2.50−2.40 (m, 1H), 2.19−2.00 (m, 2H), 1.85−1.75 (m,1H), 1.75−1.64 (m, 1H), 1.38 (s, 1H) ¹³C NMR (101 MHz, cdcl₃) δ 203.4,154.3, 136.6, 133.4, 131.8, 129.1, 127.7, 126.7, 81.2, 72.7, 67.8, 38.3,36.7, 28.1, 19.1 HRMS (ESI+): Expected 362.1130 [M+Na⁺] (C₁₇H₂₂ClNaNO₄⁺). Observed 362.1139. [α]_(D) ²⁰: −2.3° (c 1.0, chloroform).

Example 20. Preparation of(2R,6S)-2-Amino-2-(2-Chlorophenyl)-6-Hydroxycyclohexan-1-One (12A)

tert-butyl((1R,3S)-1-(2-chlorophenyl)-3-hydroxy-2-oxocyclohexyl)carbamate (11A)(860 mg, 2.5 mmol) was dissolved in dichloromethane (8.0 ml) and cooledto 0° C. Then trifluoroacetic acid (4.0 ml, 52 mmol) was added. Thereaction was stirred at 0° C. for 45 minutes. The solvent andtrifluoroacetic acid were then removed by rotary evaporation. Ethylacetate and a pH 7 saturated potassium phosphate buffer was added to thecrude material, and the material was transferred to a separatory funnel,where it was extracted with ethyl acetate twice, while keeping the pHbetween 6 and 7. The organic phase was taken and the solvent removed byrotary evaporation to give a crude white solid. This solid was purifiedby reverse phase high pressure liquid chromatography (MeCN—H₂O mobilephase with 0.1% TFA). The desired fractions were neutralized with pH 7buffer, extracted with ethyl acetate twice, and the organic phase wastaken and the solvent removed by rotary evaporation to give a whitesolid. The solid was dissolved in ethanol and the ethanol removed byrotary evaporation to give the desired product. Absolute conformationwas proven by single crystal x-ray crystallography.

¹H NMR (400 MHz, Chloroform-d) δ 7.64−7.58 (m, 1H), 7.43−7.36 (m, 1H),7.36−7.23 (m, 2H), 4.89 (dd, J=11.8, 6.5 Hz, 1H), 2.59−2.52 (m, 1H),2.46−2.42 (m, 1H), 2.22−2.08 (m, 1H), 1.98 (ddt, J=14.1, 3.9, 2.5 Hz,1H), 1.93−1.80 (m, 2H). ¹³C NMR (101 MHz, CDCl₃) δ 210.3, 141.0, 133.0,131.1, 129.1, 127.1 (2C), 72.3, 64.9, 39.4, 35.3, 19.4. HRMS (ESI+):Expected 240.0786 [M+H⁺] (C₁₂H₁₅ClNO₂ ⁺). Observed 240.0794. [α]_(D) ²⁰:+75.4° (c 1.0, chloroform)

Example 21. Preparation of (1R,3S)-3-((Tert-Butoxycarbonyl)Amino)-3-(2-Chlorophenyl)-2-Oxocyclohexyl4-Nitrobenzonate (10)

Compound 10 was synthesized using the tert-Butyl((1S,3S)-1-(2-chlorophenyl)-3-hydroxy-2-oxocyclohexyl)carbamate,compound 8 as a starting material.

¹H NMR (400 MHz, Chloroform-d) δ 8.27−8.10 (m, 2H), 7.92 (s, 2H), 7.58(d, J=7.9 Hz, 1H), 7.32 (td, J=7.6, 1.6 Hz, 1H), 7.27−7.12 (m, 2H), 6.03(s, 1H), 5.94 (dd, J=8.8, 4.9 Hz, 1H), 3.23−2.99 (m, 1H), 2.37 (dq,J=12.5, 6.2 Hz, 2H), 2.28−1.92 (m, 3H), 1.33 (s, 9H). ¹³C NMR (101 MHz,cdcl₃) δ 200.2, 163.4, 154.0, 150.7, 136.2, 134.8, 133.8, 131.4, 131.0,129.2, 128.9, 126.5, 123.4, 80.8, 76.5, 68.6, 38.1, 34.2, 28.2, 18.9.[α]_(D) ²⁰: −11° (c 1.0, chloroform).

Example 22. Preparation Tert-Butyl((1S,3R)-1-(2-Chlorophenyl)-3-Hydroxy-2-Oxocyclohexyl)Carbamate (11)

Compound was synthesized in an analogous fashion to its enantiomer(11A), using(1R,3S)-3-((tert-butoxycarbonyl)amino)-3-(2-chlorophenyl)-2-oxocyclohexyl4-nitrobenzoate as a starting material.

¹H NMR (400 MHz, Chloroform-d) δ 7.59−7.21 (m, 4H), 5.15 (s, 1H),4.71−4.55 (m, 1H), 3.63 (d, J=4.6 Hz, 1H), 3.04−2.90 (m, 1H), 2.47 (ddq,J=12.9, 6.4, 3.2 Hz, 1H), 2.23−2.00 (m, 2H), 1.95−1.68 (m, 2H), 1.39 (s,9H). ¹³C NMR (101 MHz, cdcl₃) δ 203.5, 154.4, 136.7, 133.6, 132.0,129.3, 127.9, 126.9, 72.9, 68.0, 38.5, 36.9, 28.3, 19.3, HRMS (ESI+):Expected 362.1130 [M+Na⁺] (C₁₇H₂₂ClNaNO₄ ⁺). Observed 362.1135. [α]_(D)²⁰: +1.2° (c 1.0, chloroform).

Example 23. Preparation of (2S,6R)-2-Amino-2-(2-Chlorophenyl)-6-Hydroxycyclohexan-1-One (12)

Compound 12 was synthesized in an analogous fashion to its enantiomer(12A), using tert-butyl((1S,3R)-1-(2-chlorophenyl)-3-hydroxy-2-oxocyclohexyl)carbamate as astarting material.

¹H NMR (400 MHz, Chloroform-d): 7.61 (dd, J=1.9, 7.8 Hz, 1H), 7.38 (dd,J=1.5, 7.7 Hz, 1H), 7.30 (dt, J=1.5, 7.7 Hz, 1H), 7.24 (dt, J=1.9, 7.7Hz, 1H), 4.89 (dd, J=7.0, 12 Hz, 1H), 3.52 (bs, 1H), 2.51 (dt, J=4.4 Hz,13.6 Hz, 1H), 2.48−2.40 (m, 1H), 2.22−2.07 (m, 1H), 1.99−1.82 (m, 1H),1.91−1.78 (m, 4H). ¹³C NMR (101 MHz, cdcl₃) δ 210.3, 141.3, 132.9,130.9, 128.8, 126.9 (2C), 72.0, 64.6, 39.4, 35.2, 19.4. HRMS (ESI+):Expected 240.0786 [M+H⁺] (C₁₂H₁₄ClNNaO₂ ⁺). Observed 240.0786. Rotation:−73.6° (c 1.0, chloroform).

Example 24. Recrystallization of 2R,6R-Hydroxynorketamine

100.25 grams 2R,6R-hydroxynorketamine hydrochloride was dissolved in 100mL of water.

Acetone (2000 ml) was added at rate of 0.75 equivalents (75 ml) perminute. Nucleation noted at 5 minutes, 20 seconds. The reaction wasstirred for 2 hours, then filtered and vacuum dried overnight to givethe final product in good yield.

Specific Embodiments

Embodiment 1. A crystalline form of (2R,6R)-hydroxynorketaminehydrochloride characterized by single crystal parameters approximatelyequal to the following:

cell dimensions comprising a = 7.35 Å alpha = 90° b = 7.49 Å beta =96.87° c = 11.35 Å gamma = 90° V = 621.02 Å³; and space group = P 1 211, crystal system = monoclinic, molecules per unit cell = 1, density(calculated) = 1.477 mg/m³.

Embodiment 2. The crystalline form of embodiment 1, wherein thecrystalline form contains no detectable amounts of otherhydroxynorketamine or hydroxynorketamine salts crystalline forms asdetermined by x-ray powder diffraction.

Embodiment 3. A crystalline form of (2S,6S)-hydroxynorketaminehydrochloride characterized by single crystal parameters approximatelyequal to the following:

cell dimensions comprising a = 7.35 Å alpha = 90° b = 7.48 Å beta =96.87° c = 11.34 Å gamma = 90° V = 619.32 Å³; and space group = P 1 211, crystal system = monoclinic, molecules per unit cell = 1, density(calculated) = 1.481 Mg/m³.

Embodiment 4. The crystalline form of embodiment 3, wherein thecrystalline form contains no detectable amounts of otherhydroxynorketamine or hydroxynorketamine salts crystalline forms asdetermined by x-ray powder diffraction.

Embodiment 5. A method for the chiral resolution of norketamine,comprising adding (D)-(R)-pyroglutamic acid to racemic norketamine in asolvent, forming solid (S)-norketamine D-pyroglutamate.

Embodiment 6. The method of embodiment 5, additionally comprisingconverting the (S)-norketamine D-pyroglutamate to (S)-norketamine.

Embodiment 7. A method for the chiral resolution of norketamine,comprising adding (L)-(S)-pyroglutamic acid to racemic norketamine in asolvent, forming solid (R)-norketamine L-pyroglutamate, and converting(R)-norketamine L-pyroglutamate to (R)-norketamine.

Embodiment 8. A method for the manufacture of (2R,6R)-hydroxynorketamineor (2S,6S)-hydroxynorketamine, or a salt thereof, the method comprising

treating a compound of Formula Ia or Formula Ib with a base, then with atrialkylsilylchloride, then with a peroxy compound, and then optionallywith an acid or a fluoride source, to provide a compound of Formula IIaif Formula Ia was treated or a compound of Formula IIb if Formula Ib wastreated, wherein the compound of Formula IIa or Formula IIb contains acarbamate linkage;

andcleaving the carbamate linkage in the compound of Formula IIa or FormulaIIb to provide (2R,6R)-hydroxynorketamine if the carbamate linkage ofthe compound of Formula IIa was cleaved, or (2S,6S)-hydroxynorketamineif the carbamate linkage of the compound of Formula IIb was cleaved

wherein R¹ is C₁-C₆ alkyl, C₁-C₆ haloalkyl, benzyl, 4-methoxybenzyl, or2-trimethylsilylethyl.

Embodiment 9. The method according to embodiment 8, wherein R¹ istert-butyl and wherein cleaving the carbamate linkage comprisestreatment of the compound of Formula IIa or Formula IIb with acid.

Embodiment 10. The method according to embodiment 9, wherein the acid istrifluoroacetic acid.

Embodiment 11. The method according to embodiment 8, additionallycomprising treating (2R,6R)-hydroxynorketamine with hydrochloric acid tomanufacture (2R,6R)-hydroxynorketamine hydrochloride salt, or treating(2S,6S)-hydroxynorketamine with hydrochloric acid to manufacture(2S,6S)-hydroxynorketamine hydrochloride salt.

Embodiment 12. The method according to embodiment 8 wherein the baseused for treating the compound of Formula Ia or Formula Ib with is astrong base.

Embodiment 13. The method according to embodiment 12, wherein the strongbase is lithium diisopropylamide, sodium hexamethyldisilazane, potassiumhexamethyldisilazane, or sec-butyllithium, and the compound of FormulaIa or Formula Ib is treated with the strong base at a temperature below0° C.

Embodiment 14. The method according to embodiment 8 wherein treating thecompound of Formula Ia or Formula Ib with a base comprises treating thecompound of Formula Ia or Formula Ib with lithium diisopropylamide at atemperature below −50° C.

Embodiment 15. The method according to any one of embodiments 8-14wherein the trialkylsilylchloride is trimethylsilyl chloride,triethylsilyl chloride, tert-butyldimethylsilyl chloride, ortriisopropylsilyl chloride.

Embodiment 16. The method according to embodiment 15 wherein thetrialkylsilylchloride is trimethylsilyl chloride

Embodiment 17. The method according to any one of embodiments 8-16,wherein the peroxy compound is a peroxy acid or a peroxide.

Embodiment 18. The method according to embodiment 17, wherein the peroxycompound is meta-chloroperoxybenzoic acid, peroxybenzoic acid, peraceticacid, dimethyldioxirane, tert-butylhydroperoxide, or hydrogen peroxide.

Embodiment 19. The method according to any one of embodiments 8-18,wherein after treatment with the peroxy compound the compound of FormulaIa or Formula Ib is treated with tetra-n-butylammonium fluoride.

Embodiment 20. The method according to any one of claims 8-19 whereinthe peroxy compound is meta-chloroperoxybenzoic acid.

Embodiment 21. The method according to any one of embodiments 8-20,further comprising generating the compound of Formula Ia or Formula Ibby reacting (R)-norketamine with (R¹O₂C)₂O or R¹O₂C—X to generate acompound of Formula Ia, or reacting (S)-norketamine with (R¹O₂C)₂O orR¹O₂C—X to generate a compound of Formula Ib; wherein X is a halogen.

Embodiment 22. The method according to claim 21 wherein le istert-butyl, and wherein generating the compound of Formula Ia comprisesreacting (R)-norketamine with (tert-butyl-O₂C)₂O, and generating thecompound of Formula Ib comprises reacting (S)-norketamine with(tert-butyl-O₂C)₂O.

Embodiment 23. The method according to embodiment 8, comprising

treating a compound of Formula Ia with lithium diisopropylamide at atemperature below −50° C., then with trimethylsilylchloride, then withmeta-chloroperoxybenzoic acid, and then with tetra-n-butylammoniumfluoride, to provide a compound of Formula IIa, wherein R¹ istert-butyl,

andcleaving the carbamate linkage in Formula IIa by treatment with acid toprovide (2R,6R)-hydroxynorketamine

Embodiment 24. The method according to embodiment, comprising

treating the compound of Formula Ib with lithium diisopropylamide at atemperature below −50° C., then with trimethylsilylchloride, then withmeta-chloroperoxybenzoic acid, and then with tetra-n-butylammoniumfluoride, to provide a compound of Formula IIb, wherein R¹ istert-butyl,

andcleaving the carbamate linkage in Formula IIb by treatment with acid toprovide (2S,6S)-hydroxynorketamine

Embodiment 25. A crystalline form of (2R,6R)-hydroxynorketamineexhibiting a XRPD spectra at characteristic peaks at any combination ofat least 4, of at least 5, at least 8, at least 10, or at least 12, orat least 15 of the following (20) values: 12.1, 13.6, 14.1, 15.1, 15.6,16.9, 18.0, 19.2, 19.5, 20.8, 22.1, 23.5, 24.0, 24.3, 24.6, 24.8, 25.2,26.4, 27.0, 27.4, 27.7, 28.1, 29.9, 30.2, 31.5, 31.9, 32.4, 32.7, 33.5,34.7, 36.5, 37.1, 37.7, 38.3, 38.7, 39.1, and 39.6.

Embodiment 26. A crystalline form of (2R,6R)-hydroxynorketamineexhibiting a XRPD spectra substantially as shown in FIG. 3.

1. A crystalline form of (2R,6R)-hydroxynorketamine hydrochloride or(2S,6S)-hydroxynorketamine hydrochloride wherein the crystalline form of(2R,6R)-hydroxynorketamine hydrochloride is characterized by singlecrystal parameters approximately equal to the following: cell dimensionscomprising a = 7.35 Å alpha = 90° b = 7.49 Å beta = 96.87° c = 11.35 Ågamma = 90° V = 621.02 Å³; and space group = P 1 21 1, crystal system =monoclinic, molecules per unit cell = 1, density (calculated) = 1.477mg/m³;

and wherein the crystalline form of (2S,6S)-hydroxynorketaminehydrochloride is characterized by single crystal parametersapproximately equal to the following: cell dimensions comprising a =7.35 Å alpha = 90° b = 7.48 Å beta = 96.87° c = 11.34 Å gamma = 90° V =619.32 Å³; and space group = P 1 21 1, crystal system = monoclinic,molecules per unit cell = 1, density (calculated) = 1.481 Mg/m³.


2. The crystalline form of claim 1, wherein the crystalline formcontains no detectable amounts of other hydroxynorketamine orhydroxynorketamine salts crystalline forms as determined by x-ray powderdiffraction. 3-4. (canceled)
 5. A method for the chiral resolution ofnorketamine, comprising adding (D)-(R)-pyroglutamic acid to racemicnorketamine in a solvent, forming solid (S)-norketamine D-pyroglutamateand converting the (S)-norketamine D-pyroglutamate to (S)-norketamine;or adding (L)-(S)-pyroglutamic acid to racemic norketamine in a solvent,forming solid (R)-norketamine L-pyroglutamate, and converting(R)-norketamine L-pyroglutamate to (R)-norketamine. 6-7. (canceled)
 8. Amethod for the manufacture of (2R,6R)-hydroxynorketamine or(2S,6S)-hydroxynorketamine, or a salt thereof, the method comprising

treating a compound of Formula Ia or Formula Ib with a base, then with atrialkylsilylchloride, then with a peroxy compound, and then optionallywith an acid or a fluoride source, to provide a compound of Formula IIaif Formula Ia was treated or a compound of Formula IIb if Formula Ib wastreated, wherein the compound of Formula IIa or Formula IIb contains acarbamate linkage;

and cleaving the carbamate linkage in the compound of Formula IIa orFormula IIb to provide (2R,6R)-hydroxynorketamine if the carbamatelinkage of the compound of Formula IIa was cleaved, or(2S,6S)-hydroxynorketamine if the carbamate linkage of the compound ofFormula IIb was cleaved

wherein R¹ is C₁-C₆ alkyl, C₁-C₆ haloalkyl, benzyl, 4-methoxybenzyl, or2-trimethylsilylethyl.
 9. The method according to claim 8, wherein R¹ istert-butyl and wherein cleaving the carbamate linkage comprisestreatment of the compound of Formula IIa or Formula IIb with acid. 10.The method according to claim 9, wherein the acid is trifluoroaceticacid.
 11. The method according to claim 8, additionally comprisingtreating (2R,6R)-hydroxynorketamine with hydrochloric acid tomanufacture (2R,6R)-hydroxynorketamine hydrochloride salt, or treating(2S,6S)-hydroxynorketamine with hydrochloric acid to manufacture(2S,6S)-hydroxynorketamine hydrochloride salt.
 12. (canceled)
 13. Themethod according to claim, wherein the base is a strong base which islithium diisopropylamide, sodium hexamethyldisilazane, potassiumhexamethyldisilazane, or sec-butyllithium, and the compound of FormulaIa or Formula Ib is treated with the base at a temperature below 0° C.14. The method according to claim 8 wherein treating the compound ofFormula Ia or Formula Ib with a base comprises treating the compound ofFormula Ia or Formula Ib with lithium diisopropylamide at a temperaturebelow −50° C.
 15. The method according to claims 8 wherein thetrialkylsilylchloride is trimethylsilyl chloride, triethylsilylchloride, tert-butyldimethylsilyl chloride, or triisopropylsilylchloride.
 16. The method according to claim 15 wherein thetrialkylsilylchloride is trimethylsilyl chloride
 17. The methodaccording to claim 8, wherein the peroxy compound is a peroxy acid or aperoxide.
 18. The method according to claim 17, wherein the peroxycompound is meta-chloroperoxybenzoic acid, peroxybenzoic acid, peraceticacid, dimethyldioxirane, tert-butylhydroperoxide, or hydrogen peroxide.19. The method according to claim 8, wherein after treatment with theperoxy compound the compound of Formula Ia or Formula Ib is treated withtetra-n-butylammonium fluoride.
 20. (canceled)
 21. The method accordingto claim 8, further comprising generating the compound of Formula Ia orFormula Ib by reacting (R)-norketamine with (R¹O₂C)₂O or R¹O₂C—X togenerate a compound of Formula Ia, or reacting (S)-norketamine with(R¹O₂C)₂ O or R¹O₂C—X to generate a compound of Formula Ib; wherein X isa halogen.
 22. The method according to claim 21 wherein R¹ istert-butyl, and wherein generating the compound of Formula Ia comprisesreacting (R)-norketamine with (tert-butyl-O₂C)₂O, and generating thecompound of Formula Ib comprises reacting (S)-norketamine with(tert-butyl-O₂C)₂O.
 23. The method according to claim 8, comprising

Treating a compound of Formula Ia with lithium diisopropylamide at atemperature below −50° C., then with trimethylsilylchloride, then withmeta-chloroperoxybenzoic acid, and then with tetra-n-butylammoniumfluoride, to provide a compound of Formula IIa, wherein R¹ istert-butyl,

and cleaving the carbamate linkage in Formula IIa by treatment with acidto provide (2R,6R)-hydroxynorketamine


24. The method according to claim 8, comprising

treating the compound of Formula Ib with lithium diisopropylamide at atemperature below −50° C., then with trimethylsilylchloride, then withmeta-chloroperoxybenzoic acid, and then with tetra-n-butylammoniumfluoride, to provide a compound of Formula IIb, wherein R¹ istert-butyl,

and cleaving the carbamate linkage in Formula IIb by treatment with acidto provide (2S,6S)-hydroxynorketamine


25. A crystalline form of (2R,6R)-hydroxynorketamine exhibiting a XRPDspectra with characteristic peaks at any combination of at least 5, atleast 8, at least 10, or at least 12 of the following (2θ) values:12.1,13.6, 14.1, 15.1, 15.6, 16.9, 18.0, 19.2, 19.5, 20.8, 22.1, 23.5, 24.0,24.3, 24.6, 24.8, 25.2, 26.4, 27.0, 27.4, 27.7, 28.1, 29.9, 30.2, 31.5,31.9, 32.4, 32.7, 33.5, 34.7, 36.5, 37.1, 37.7, 38.3, 38.7, 39.1, and39.6.
 26. A crystalline form of (2R,6R)-hydroxynorketamine of claim 25,exhibiting a XRPD spectra substantially as shown in FIG. 3.